Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors

ABSTRACT

Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-Beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure: 
                         
enantiomers, diastereomers, solvates, or salts thereof, wherein A, W, X and Z are defined herein.

CROSS-REFERENCES TO RELATED APPLICATION

This application claims priority benefit under Title 35 §119(e) of U.S.provisional Application No. 60/840,071, filed Aug. 24, 2006, thecontents of which are herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The steroid hormone cortisol is a key regulator of many physiologicalprocesses. However, an excess of cortisol, as occurs in Cushing'sDisease, provokes severe metabolic abnormalities including: type 2diabetes, cardiovascular disease, obesity, and osteoporosis. Manypatients with these diseases, however, do not show significant increasesin plasma cortisol levels. In addition to plasma cortisol, individualtissues can regulate their glucocorticoid tone via the in situconversion of inactive cortisone to the active hormone cortisol. Indeed,the normally high plasma concentration of cortisone provides a readysupply of precursor for conversion to cortisol via the intracellularenzyme 11-beta-hydroxysteroid dehydrogenase type I (11beta-HSD1).

11beta-HSD1 is a member of the short chain dehydrogenase superfamily ofenzymes. By catalyzing the conversion of cortisone to cortisol,11beta-HSD1 controls the intracellular glucocorticoid tone according toits expression and activity levels. In this manner, 11beta-HSD1 candetermine the overall metabolic status of the organ. 11beta-HSD1 isexpressed at high levels in the liver and at lower levels in manymetabolically active tissues including the adipose, the CNS, thepancreas, and the pituitary. Taking the example of the liver, it ispredicted that high levels of 11beta-HSD1 activity will stimulategluconeogenesis and overall glucose output. Conversely, reduction of11beta-HSD1 activity will downregulate gluconeogenesis resulting inlower plasma glucose levels.

Various studies have been conducted that support this hypothesis. Forexample, transgenic mice expressing 2× the normal level of 11beta-HSD1in only the adipose tissue show abdominal obesity, hyperglycemia, andinsulin resistance. (H. Masuzaki, J. Paterson, H. Shinyama, N. M.Morton, J. J. Mullins, J. R. Seckl, J. S. Flier, “A Transgenic Model ofVisceral Obesity and the Metabolic Syndrome”, Science, 294:2166-2170(2001). Conversely, when the 11beta-HSD1 gene is ablated by homologousrecombination, the resulting mice are resistant to diet induced obesityand the accompanying dysregulation of glucose metabolism (N. M. Morton,J. M. Paterson, H. Masuzaki, M. C. Holmes, B. Staels, C. Fievet, B. R.Walker, J. S. Flier, J. J. Mullings, J. R. Seckl, “Novel AdiposeTissue-Mediated Resistance to Diet-induced Visceral Obesity in11β-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice”, Diabetes,53:931-938 (2004). In addition, treatment of genetic mouse models ofobesity and diabetes (ob/ob, db/db and KKAy mice) with a specificinhibitor of 11beta-HSD1 causes a decrease in glucose output from theliver and an overall increase in insulin sensitivity (P. Alberts, C.Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norling, G.Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, C. E. Nilsson, M.Fiedler, E. Bergqvist, B. Ohman, E. Bjorkstrand, L. B. Abrahmsen,“Selective Inhibition of 11β-Hydroxysteroid Dehydrogenase Type IImproves Hepatic Insuling Sensitivity in Hyperglycemic Mice Strains”,Endocrinology, 144:4755-4762 (2003)). Furthermore, inhibitors of11beta-HSD1 have been shown to be effective in treating metabolicsyndrome and atherosclerosis in high fat fed mice (Hermanowski-Vosatkaet al., J. Exp. Med., 202(4):517-527 (2002)). Based in part on thesestudies, it is believed that local control of cortisol levels isimportant in metabolic diseases in these model systems. In addition, theresults of these studies also suggest that inhibition of 11beta-HSD1will be a viable strategy for treating metabolic diseases such as type 2diabetes, obesity, and the metabolic syndrome.

Lending further support to this idea are the results of a series ofpreliminary clinical studies. For example, several reports have shownthat adipose tissue from obese individuals has elevated levels of11beta-HSD1 activity. In addition, studies with carbenoxolone, a naturalproduct derived from licorice that inhibits both 11beta-HSD1 and11beta-HSD2 (converts cortisol to cortisone in kidney) have shownpromising results. A seven day, double blind, placebo controlled, crossover study with carbenoxolone in mildly overweight individuals with type2 diabetes showed that patients treated with the inhibitor, but not theplacebo group, displayed a decrease in hepatic glucose production (R. C.Andrews, O. Rooyackers, B. R. Walker, J. Clin. Endocrinol. Metab.,88:285-291 (2003)). This observation is consistent with the inhibitionof 11beta-HSD1 in the liver. The results of these preclinical and earlyclinical studies strongly support the concept that treatment with apotent and selective inhibitor of 11beta-HSD1 will be an efficacioustherapy in patients afflicted with type 2 diabetes, obesity, and themetabolic syndrome.

SUMMARY OF THE INVENTION

In accordance with the present invention, compounds are provided thathave the general structure of formula I:

wherein m, A, X, W and Z are defined below.

The compounds of the present invention inhibit the activity of theenzyme 11-beta-hydroxysteroid dehydrogenase type I. Consequently, thecompounds of the present invention may be used in the treatment ofmultiple diseases or disorders associated with 11-beta-hydroxysteroiddehydrogenase type I, such as diabetes and related conditions,microvascular complications associated with diabetes, the macrovascularcomplications associated with diabetes, cardiovascular diseases,Metabolic Syndrome and its component conditions, inflammatory diseasesand other maladies. Examples of diseases or disorders associated withthe activity of the enzyme 11-beta-hydroxysteroid dehydrogenase type Ithat can be prevented, inhibited, or treated according to the presentinvention include, but are not limited to, diabetes, hyperglycemia,impaired glucose tolerance, insulin resistance, hyperinsulinemia,retinopathy, neuropathy, nephropathy, delayed wound healing,atherosclerosis and its sequelae (acute coronary syndrome, myocardialinfarction, angina pectoris, peripheral vascular disease, intermitantclaudication), abnormal heart function, myocardial ischemia, stroke,Metabolic Syndrome, hypertension, obesity, dislipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy, glaucoma and inflammatory diseases, such as, rheumatoidarthritis, Cushing's Disease, Alzheimer's Disease and osteoarthritis.

The present invention provides for compounds of formula I,pharmaceutical compositions employing such compounds, and for methods ofusing such compounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of formula I, alone or in combination with apharmaceutically acceptable carrier.

Further, in accordance with the present invention, a method is providedfor preventing, inhibiting, or treating the progression or onset ofdiseases or disorders associated with the activity of the enzyme11-beta-hydroxysteroid dehydrogenase type I, such as defined above andhereinafter, wherein a therapeutically effective amount of a compound offormula I is administered to a mammalian, i.e., human, patient in needof treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Further, the present invention provides a method for preventing,inhibiting, or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of formula I and another compound of formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human, patient in need of treatment.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of formula I areprovided

enantiomers, diastereomers, solvates, or salts thereof wherein:

A is a 5- to 20-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, —C(═O)C(═O)OH, —C(═O)NR₉R₉, tetrazolyl, or—C(═O)NHS(O)₂R₉;

W is absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b)—)_(m)—O—,(—CR_(8a)R_(8b)—)_(m)—N(R₁₄)—, C₃₋₆ cycloalkyl, alkenyl or alkynyl,wherein the cycloalkyl or alkenyl may be optionally substituted with oneor more R_(8a)'s;

m is 1-3;

Z is —CN, C₃₋₁₀ alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, all of which may be optionally substituted with oneor more R₄'s, and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, orheterocyclyl may be optionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl maybe optionally substituted with one or more R_(9a)'s; or

R_(8a) and R_(8b) are taken together with the carbon to which both areattached to form a 3- to 7-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith 0-3 R_(9a);

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₄,

—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄,—C(═NR₁₄)NR₁₄R₁₄, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄,—NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄,—NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl, cycloalkyl,cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3R_(10a), and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —C(═NR₁₄)NR₁₄R₁₄, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ or arylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl orarylalkyl may be optionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —C(═NR₁₅)NR₁₅R₁₅, —NHC(═NR₁₅)NR₁₅R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅,—NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ or arylalkyl;

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl; and

provided that:

(i) when W is absent, Z is phenyl, X is —C(═O)OH, lower alkyl ortetrazolyl, A is not bicyclo(2,2,1)heptanyl, bicyclo(2,2,1)heptenyl,bicyclo(2,2,2)octanyl, or bicyclo(2,2,2)octenyl;

(ii) when W is absent, Z is optionally substituted phenyl, orheterocyclyl, X is —C(═O)OH or —C(═O)NR₉R₉ and R₉ is hydrogen or loweralkyl, A is not 8-azabicyclo(3.2.1)octanyl;

(iii) the compound is not a compound of the following structure:

wherein R is optionally substituted phenyl;

(iv) the compound is not a compound of the following structure:

(v) the compound is not a compound of the following structure:

(vi) the compound is not a compound of the following structure:

(vii) the compound is not a compound of the following structure:

In another embodiment, compounds of formula I are those in which A is a5- to 20-membered non-aromatic bi-, tri- or polycyclic ring systemoptionally containing 1-3 heteroatoms selected from N, O, S, S(O) andS(O)₂, which is substituted with at least one R₄.

In another embodiment, compounds of formula I are those in which:

A is a 6- to 15-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, —C(═O)C(═O)OH, —C(═O)NR₉R₉, or tetrazolyl;

W is absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b)—)_(m)—O—,(—CR_(8a)R_(8b)—)_(m)—N(R₁₄)—, or alkenyl, wherein the alkenyl may beoptionally substituted with one or more R_(8a)'s;

m is 1-3;

Z is CN, C₃₋₁₀ alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, all of which may be optionally substituted with oneor more R₄'s, and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, orheterocyclyl may be optionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl maybe optionally substituted with one or more R_(9a)'s; or

R_(8a) and R_(8b) are taken together with the carbon to which both areattached to form a 3- to 7-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith 0-3 R_(9a);

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3R_(10a), and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl orarylalkyl may be optionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl.

In yet another embodiment, compounds of formula I are those in which:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, —C(═O)NR₉R₉, or tetrazolyl;

W is absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b)—)_(m)—O— or alkenyl,wherein the alkenyl may be optionally substituted with one or moreR_(8a)'s;

m is 1-2;

Z is CN, C₃₋₁₀ alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, all of which may be optionally substituted with oneor more R₄'s, and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, orheterocyclyl may be optionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl maybe optionally substituted with one or more R_(9a)'s; or

R_(8a) and R_(8b) are taken together with the carbon to which both areattached to form a 3- to 7-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith 0-3 R_(9a);

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3R_(10a), and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl orarylalkyl may be optionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl.

In another embodiment, compounds of formula I are those in which:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, —C(═O)NR₉R₉, or tetrazolyl;

W is absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O— or alkenyl,wherein the alkenyl may be optionally substituted with one or moreR_(8a)'s;

m is 1-2;

Z is cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, allof which may be optionally substituted with one or more R₄'s, and theheterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, orheterocyclyl may be optionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl maybe optionally substituted with one or more R_(9a)'s; or

R_(8a) and R_(8b) are taken together with the carbon to which both areattached to form a 3- to 7-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith 0-3 R_(9a);

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3R_(10a), and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl orarylalkyl may be optionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl.

In still yet another embodiment, compounds of formula I are those inwhich:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, —C(═O)NR₉R₉, or tetrazolyl;

W is absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O— or alkenyl,wherein the alkenyl may be optionally substituted with one or moreR_(8a)'s;

m is 1-2;

Z is aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, all of whichmay be optionally substituted with one or more R₄'s, and theheterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, orheterocyclyl may be optionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl maybe optionally substituted with one or more R_(9a)'s; or

R_(8a) and R_(8b) are taken together with the carbon to which both areattached to form a 3- to 7-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith 0-3 R_(9a);

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl may be optionally substituted with 0-3R_(10a), and the heterocyclyl and heterocyclylalkyl contain 1-4heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl orarylalkyl may be optionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl.

In one embodiment, compounds of formula I are those in which:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, —C(═O)NR₉R₉, or tetrazolyl;

W is absent, (—CR_(8a)R_(8b)—)_(m), —(—CR_(8a)R_(8b))_(m)—O— or alkenyl,wherein the alkenyl may be optionally substituted with one or moreR_(8a)'s;

m is 1-2;

Z is aryl, arylalkyl or heterocyclylalkyl, all of which may beoptionally substituted with one or more R₄'s, and the heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, alkenyl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, cycloalkyl, orheterocyclyl may be optionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl maybe optionally substituted with one or more R_(9a)'s; or

R_(8a) and R_(8b) are taken together with the carbon to which both areattached to form a 3- to 7-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith 0-3 R_(9a);

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄,—OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, alkenyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl,wherein the alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-3 R_(10a), andthe heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selectedfrom N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl orarylalkyl may be optionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃,—OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl.

In still yet another embodiment, compounds of formula I are those inwhich:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, or —C(═O)NR₉R₉;

W is absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O— or alkenyl,wherein the alkenyl may be optionally substituted with one or moreR_(8a)'s;

m is 1-2;

Z is aryl, arylalkyl or heterocyclylalkyl, all of which may beoptionally substituted with one or more R₄'s, and the heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl or heterocyclyl may beoptionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl maybe optionally substituted with one or more R_(9a)'s; or

R_(8a) and R_(8b) are taken together with the carbon to which both areattached to form a 3- to 7-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith 0-3 R_(9a);

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl or heterocyclyl may be optionallysubstituted with 0-5 R_(9a), and the heterocyclyl contains 1-4heteroatoms selected from N, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄,—OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-3 R_(10a), andthe heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selectedfrom N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl orarylalkyl may be optionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃,—OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, aryl or arylalkyl.

In another embodiment, compounds of formula I are those compounds inwhich:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, or —C(═O)NR₉R₉;

W is absent, (—CR_(8a)R_(8b)—)_(m) or (—CR_(8a)R_(8b))_(m)—O—;

m is 1-2;

Z is aryl, arylalkyl or heterocyclylalkyl, all of which may beoptionally substituted with one or more R₄'s, and the heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl, or heterocyclyl may beoptionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀ or —C(═O)NR₉R₉, wherein the alkyl may beoptionally substituted with one or more R_(9a)'s; or

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl or heterocyclyl may be optionallysubstituted with 0-5 R_(9a), and the heterocyclyl contains 1-4heteroatoms selected from N, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄,—OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-3 R_(10a), andthe heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selectedfrom N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, or aryl, wherein the alkyl, cycloalkyl or aryl may beoptionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃,—OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl or aryl.

In another embodiment, compounds of formula I are those compounds inwhich:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)OH, or —C(═O)NR₉R₉;

W is absent, (—CR_(8a)R_(8b)—)_(m) or —(CR_(8a)R_(8b))_(m)—O—;

m is 1-2;

Z is aryl or arylalkyl, both of which may be optionally substituted withone or more R₄'s;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl, or heterocyclyl may beoptionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, —NH₂,—CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀,—NR₉C(═O)OR₈ or —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀ or —C(═O)NR₉R₉, wherein the alkyl may beoptionally substituted with one or more R_(9a)'s; or

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl orheterocyclyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl contains 1-4 heteroatoms selected from N, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, ═O,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀,—OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl,cycloalkyl, cycloalkylalkyl and heterocyclyl may be optionallysubstituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-3 R_(10a), andthe heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selectedfrom N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, —NH₂,—CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ or arylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl, or aryl, wherein the alkyl, cycloalkyl or aryl may beoptionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, —NH₂,—CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅,—C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃,—C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅,—C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅, —S(═O)R₁₅,—S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ or arylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl or aryl.

In another embodiment, compounds of formula I are those compounds inwhich:

A is a 7- to 14-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which may be optionally substituted with one or more R₄'s;

X is —C(═O)NR₉R₉;

W is absent, (—CR_(8a)R_(8b)—)_(m) or —(CR_(8a)R_(8b))_(m)—O—;

m is 1-2;

Z is aryl or arylalkyl, both of which may be optionally substituted withone or more R₄'s;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl or heterocyclyl may beoptionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen, alkyl or aryl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀ or —C(═O)NR₉R₉, wherein the alkyl may beoptionally substituted with one or more R_(9a)'s; or

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl orheterocyclyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl contains 1-4 heteroatoms selected from N, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀,—S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄,—NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄,—NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl, cycloalkyl andheterocyclyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a), and the heterocyclyl and heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄,—S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ or arylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl or aryl, wherein the alkyl, cycloalkyl or aryl may beoptionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅,—NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅,—S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃,—C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅,—NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ or arylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl or aryl.

In another embodiment, compounds of formula I are those compounds inwhich:

A is a 7- to 12-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which is substituted with one or more R₄'s;

X is —C(═O)NR₉R₉;

W is absent or (—CR_(8a)R_(8b)—)_(m);

m is 1-2;

Z is aryl or arylalkyl, both of which may be optionally substituted withone or more R₄'s;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl, or heterocyclyl may beoptionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl, aryl or heterocyclyl;

R_(8a), at each occurrence, is independently hydrogen or alkyl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, —OR₁₀ or —C(═O)NR₉R₉, wherein the alkyl may beoptionally substituted with one or more R_(9a)'s; or

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl or heterocyclyl, wherein the alkyl, cycloalkyl, aryl orheterocyclyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl contains 1-4 heteroatoms selected from N, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀,—S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄,—NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄,—NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl, cycloalkyl andheterocyclyl may be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl, aryl,arylalkyl or heterocyclyl, wherein the alkyl, aryl, arylalkyl orheterocyclyl may be optionally substituted with 0-3 R_(10a), and theheterocyclyl contains 1-4 heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄,—S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ or arylalkyl;

R₁₄, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl or aryl, wherein the alkyl, cycloalkyl or aryl may beoptionally substituted with 0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅,—NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅,—S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃,—C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅,—NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ or arylalkyl; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkyl,cycloalkyl or aryl.

In another embodiment, compounds of formula I are those compounds inwhich:

A is a 7- to 12-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which is substituted with one or more R₄'s;

X is —C(═O)NR₉R₉;

W is absent or (—CR_(8a)R_(8b)—)_(m);

m is 1;

Z is aryl or arylalkyl, both of which may be optionally substituted withone or more R₄'s;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl or heterocyclyl may beoptionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl or aryl;

R_(8a), at each occurrence, is independently hydrogen or alkyl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN or —OR₁₀, wherein the alkyl may be optionally substitutedwith one or more R_(9a)'s; or

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy, arylor heterocyclyl, wherein the alkyl, aryl or heterocyclyl may beoptionally substituted with 0-5 R_(9a), and the heterocyclyl contains1-4 heteroatoms selected from N, O, and S; or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀,—S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄,—NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, or—NR₁₄C(═O)NR₁₄R₁₄, wherein the alkyl, aryl, cycloalkyl and heterocyclylmay be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl, aryl orheterocyclyl, wherein the alkyl, aryl or heterocyclyl may be optionallysubstituted with 0-3 R_(10a), and the heterocyclyl and heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S;

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄,—S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, or —NR₁₄S(O₂)R₈;

R₁₄, at each occurrence, is independently selected from hydrogen, alkylor aryl, wherein the alkyl or aryl may be optionally substituted with0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅,—NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅,—S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃,—C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅,—NR₁₅C(═O)OR₈, or —NR₁₅S(O₂)R₈; and

R₁₅, at each occurrence, is independently selected from hydrogen, alkylor aryl.

In another embodiment, compounds of formula I are those compounds inwhich:

A is a 7- to 10-membered non-aromatic bi-, tri- or polycyclic ringsystem optionally containing 1-3 heteroatoms selected from N, O, S, S(O)and S(O)₂, which is substituted with one or more R₄'s;

X is —C(═O)NR₉R₉;

W is absent or (—CR_(8a)R_(8b)—)_(m);

m is 1;

Z is aryl or arylalkyl, both of which may be optionally substituted withone or more R₄'s;

provided that W and Z, or when W is absent, X and Z, are attached to thesame carbon on Ring A;

R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl or heterocyclyl may beoptionally substituted with one or more R₅'s;

R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈;

R₈, at each occurrence, is independently alkyl or aryl;

R_(8a), at each occurrence, is independently hydrogen or alkyl;

R_(8b), at each occurrence, is independently hydrogen, —C(═O)OH, alkyl,—OH, halo, —CN, or —OR₁₀;

R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy oraryl, wherein the alkyl or aryl may be optionally substituted with 0-5R_(9a); or

two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s;

R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀,—S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄,—NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, or—NR₁₄C(═O)NR₁₄R₁₄, wherein the alkyl, aryl, cycloalkyl and heterocyclylmay be optionally substituted with 0-3 R_(10a);

R₁₀, at each occurrence, is independently selected from alkyl or aryl,wherein the alkyl or aryl may be optionally substituted with 0-3R_(10a);

R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄,—S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, or —NR₁₄S(O₂)R₈;

R₁₄, at each occurrence, is independently selected from hydrogen, alkylor aryl, wherein the alkyl or aryl may be optionally substituted with0-3 R_(14a);

R_(14a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅,—NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅,—S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃,—C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅,—NR₁₅C(═O)OR₈, or —NR₁₅S(O₂)R₈; and

R₁₅, at each occurrence, is independently selected from hydrogen oralkyl.

In another embodiment, compounds of the present invention are selectedfrom the compounds exemplified in the examples.

In another embodiment, the present invention relates to pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound of the present invention, alone or, optionally, in combinationwith a pharmaceutically acceptable carrier and/or one or more otheragent(s).

In another embodiment, the present invention relates to methods ofinhibiting the activity of the enzyme 11-beta-hydroxysteroiddehydrogenase type I comprising administering to a mammalian patient,for example, a human patient, in need thereof a therapeuticallyeffective amount of a compound of the present invention, alone, oroptionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of diseasesor disorders associated with the activity of the enzyme11-beta-hydroxysteroid dehydrogenase type I comprising administering toa mammalian patient, for example, a human patient, in need ofprevention, inhibition, or treatment a therapeutically effective amountof a compound of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

Examples of diseases or disorders associated with the activity of theenzyme 11-beta-hydroxysteroid dehydrogenase type I that can beprevented, inhibited, or treated according to the present inventioninclude, but are not limited to, diabetes, hyperglycemia, impairedglucose tolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, delayed wound healing, atherosclerosis, acutecoronary syndrome, myocardial infarction, angina pectoris, peripheralvascular disease, intermitant claudication, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dislipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy, glaucoma, rheumatoidarthritis, Cushing's Disease, Alzheimer's Disease and osteoarthritis.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdiabetes, hyperglycemia, obesity, dislipidemia, hypertension, cognitiveimpairment, rheumatoid arthritis, osteoarthritis, glaucoma, Cushing'sDisease and Metabolic Syndrome comprising administering to a mammalianpatient, for example, a human patient, in need of prevention,inhibition, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In still another embodiment, the present invention relates to a methodfor preventing, inhibiting, or treating the progression or onset ofdiabetes, comprising administering to a mammalian patient, for example,a human patient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In yet still another embodiment, the present invention relates to amethod for preventing, inhibiting, or treating the progression or onsetof hyperglycemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of obesitycomprising administering to a mammalian patient, for example, a humanpatient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In one embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofdislipidemia comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofhypertension comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofcognitive impairment comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofrheumatoid arthritis comprising administering to a mammalian patient,for example, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofosteoarthritis comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofMetabolic Syndrome comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset of glaucomacomprising administering to a mammalian patient, for example, a humanpatient, in need of prevention, inhibition, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention relates to a method forpreventing, inhibiting, or treating the progression or onset ofCushing's Disease comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, inhibition, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In one embodiment, the present invention provides a process for thepreparation of a compound of Formula Ih or Ii

wherein A, X, W and Z are as defined above;comprising reducing a racemic compound of Formula If

with an enzymatic reductase, such as a ketoreductase, produced by amicroorganism from the group consisting of Pichia, Hansenula, Candida orRhodotorula.

In one embodiment, the strain of Pichia is Pichia membranafaciens,Pichia anomala, Pichia ciferrii or Pichia silvicola. In anotherembodiment, the strain of Hansenula is Hansenula fabiani or Hansenulapolymorpha. In a further embodiment, the strain of Candida is Candidautilis or Candida boidini. In yet a further embodiment, the strain ofRhodotorula is Rhodotorula glutinis.

In another embodiment, processes for preparing compounds of formula Ihor Ii are provided wherein the reduction with an enzyme is carried outeither by:

introducing a ketone compound of formula If into a medium in which themicroorganism is being fermented to form a reaction mixture in which theenzyme is concurrently being formed and reduces the racemic compound; or

fermenting the microorganism until sufficient growth is realized, and

introducing the racemic compound to the microorganism in which theketone compound of formula If is reduced with the enzyme.

In still another embodiment, processes for preparing compounds offormula Ih or Ii are provided wherein the amount of the ketone compoundof formula If added to the reaction mixture is up to about 50 g/L of thereaction mixture.

In still yet another embodiment, processes for preparing compounds offormula Ih or Ii are provided wherein an enzyme is isolated andoptionally purified.

In one embodiment, processes for preparing compounds of formula Ih or Iiare provided wherein the reduction by an enzyme is carried out byreacting the ketone compound of formula If with the enzyme that waspreviously isolated and optionally purified before contacting with theketone compound.

In another embodiment, processes for preparing compounds of formula Ihor Ii are provided wherein the enzyme is derived from cell extracts.

In still yet another embodiment, processes for preparing compounds offormula Ih or Ii are provided wherein the enzyme is obtained fromHansenula fabiani. In one embodiment, the enzyme is obtained fromHansenula fabiani strain SC13894 (ATCC 58045).

In another embodiment, processes for preparing compounds of formula Ihor Ii are provided wherein the enzyme provides a reaction yield ofgreater than 60% by weight of the compound of formula Ih or Ii, based onthe weight of the ketone input.

In still another embodiment, processes for preparing compounds offormula Ih or Ii are provided wherein the process provides the compoundsof formula Ih or Ii in an enantiomeric excess greater than 95%.

In yet another embodiment, processes for preparing compounds of formulaIh or Ii are provided wherein the reduction by an enzyme is carried outat a pH of between about 5.0 and about 9.0.

In one embodiment, the present invention provides processes for thepreparation of an enzyme for the preparation of compounds of formula Ihor Ii from a compound of formula If comprising:

(a) either

-   -   (i) providing a microorganism selected from the group consisting        of Pichia, Hansenula, Candida or Rhodotorula in a growth medium        under conditions which allow for expression of an enzyme, or    -   (ii) introducing a gene which encodes for the enzyme into a host        microorganism for recombinant expression, introducing the host        microorganism in a growth medium under conditions which allow        for expression of the enzyme and allowing it to grow and express        the enzyme;

(b) optionally, extracting the enzyme from the growth medium; and

(c) optionally, purifying the enzyme.

In another embodiment, processes for the preparation of an enzyme forthe preparation of compounds of formula Ih or Ii are provided whereinthe process of extracting the enzyme comprises lysing the cells of themicroorganism and isolating the enzyme.

In still another embodiment, processes for the preparation of an enzymefor the preparation of compounds of formula Ih or Ii are providedwherein the processes of purifying the enzyme comprises ion-exchange,hydrophobic, and hydroxyapatite chromatography.

In one embodiment, processes for preparing compounds of formula Ih or Iiare provided wherein

(a) either

-   -   (i) providing a microorganism in a growth medium under        conditions which allow for expression of an enzyme, or    -   (ii) introducing a gene which encodes for the enzyme into a host        microorganism for recombinant expression, introducing the host        microorganism in a growth medium under conditions which allow        for expression of the enzyme and allowing it to grow and express        the enzyme; and

(b) reacting the enzyme with a compound of formula If to produce thedesired compounds.

In another embodiment, the present invention provides processes forpreparing a compound of formula Ih which comprises reacting a compoundof the formula If with NADP or NADPH, glucose dehydrogenase, glucose,and a ketoreductase to afford Compound Ih or Ii.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment may be combined with any andall other elements from any of the embodiments to describe additionalembodiments.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

One enantiomer of a compound of Formula I may display superior activitycompared with the other. Thus, all of the stereochemistries areconsidered to be a part of the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column or by a resolution using a resolving agent such ascamphonic chloride as in Steven D. Young et al., Antimicrobial Agentsand Chemotherapy, 2602-2605 (1995).

To the extent that compounds of the formula I, and salts thereof, mayexist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's or ringatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O), then 2hydrogens on the atom are replaced.

When any variable (e.g., R₄) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with (R₄)_(m) and m is0-3, then said group may optionally be substituted with up to three R₄groups and R₄ at each occurrence is selected independently from thedefinition of R₄. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups containing 1 to 20carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, inthe normal chain, such as methyl, ethyl, propyl, isopropyl, butyl,t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, thevarious branched chain isomers thereof, and the like as well as suchgroups may optionally include 1 to 4 substituents such as halo, forexample F, Br, Cl, or I, or CF₃, alkyl, alkoxy, aryl, aryloxy,aryl(aryl) or diaryl, arylalkyl, arylalkyloxy, alkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl,heteroaryl, heteroaryloxy, heteroarylalkyl, heteroarylalkoxy,aryloxyalkyl, alkylthio, arylalkylthio, aryloxyaryl, alkylamido,alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, haloalkyl,trihaloalkyl, and/or alkylthio.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons, and morepreferably 1 to 8 carbons in the normal chain, which include one to sixdouble bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl,4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonyl-amino, nitro, cyano, thiol, alkylthio, and/or any of thealkyl substituents set out herein.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons and morepreferably 2 to 8 carbons in the normal chain, which include one triplebond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl,4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl,and the like, and which may be optionally substituted with 1 to 4substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the alkylsubstituents set out herein.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 10 rings, preferably 1 to 3 rings, including monocyclicalkyl, bicyclic alkyl (or bicycloalkyl) and tricyclic alkyl, containinga total of 3 to 20 carbons forming the ring, preferably 3 to 15 carbons,more preferably 3 to 10 carbons, forming the ring and which may be fusedto 1 or 2 aromatic rings as described for aryl, which includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents for alkyl.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

Unless otherwise indicated, the term “aryl” as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl, including 1-naphthyl and 2-naphthyl) and may optionallyinclude 1 to 3 additional rings fused to a carbocyclic ring or aheterocyclic ring (such as aryl, cycloalkyl, heteroaryl, orcycloheteroalkyl rings

for example

and may be optionally substituted through available carbon atoms with 1,2, or 3 substituents, for example, hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl, or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino,or arylsulfonaminocarbonyl, and/or any of the alkyl substituents set outherein.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl, or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “amino” as employed herein alone oras part of another group refers to amino that may be substituted withone or two substituents, which may be the same or different, such asalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may befurther substituted with a carboxylic acid and/or any of the R¹ groupsor substituents for R¹ as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl, or hydroxy.

Unless otherwise indicated, the term “lower alkylthio,” “alkylthio,”“arylthio,” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl, or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino,” “alkylamino,”“arylamino,” or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl, or arylalkyl groupslinked to a nitrogen atom.

As used herein, the term “heterocyclyl”, “heterocyclic system” or“heterocyclic ring” is intended to mean a stable 3- to 14-memberedmonocyclic, bicyclic or tricyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom, which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoindolyl, piperidinyl,piperidonyl, 4-piperidonyl, piperonyl, pyrazolyl, 1,2,4-triazolyl,1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, andpyrimidinyl. Also included are fused ring and spiro compoundscontaining, for example, the above heterocycles.

Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,tetrazolyl, and xanthenyl. In another aspect of the invention, examplesof heteroaryls are indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

The term “heterocyclylalkyl” or “heterocyclyl” as used herein alone oras part of another group refers to heterocyclyl groups as defined abovelinked through a C atom or heteroatom to an alkyl chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to an alkyl chain, alkylene,or alkenylene as defined above.

The term “cyano” as used herein, refers to a —CN group.

The term “nitro” as used herein, refers to an —NO₂ group.

The term “hydroxy” as used herein, refers to an OH group.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,p. 1418, (1985), the disclosure of which is hereby incorporated byreference.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrugs” as employed herein includes esters and carbonatesformed by reacting one or more hydroxyls of compounds of formula I withalkyl, alkoxy, or aryl substituted acylating agents employing proceduresknown to those skilled in the art to generate acetates, pivalates,methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

-   a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al.,    Ch. 31, (Academic Press, 1996);-   b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson    and H. Bundgaard, eds. Ch. 5, pp. 113-191 (Harwood Academic    Publishers, 1991); and-   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and    Joachim M. Mayer, (Wiley-VCH, 2003).    Said references are incorporated herein by reference.

In addition, compounds of the formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents and/orexhibit polymorphism. Consequently, compounds of formula I can exist inenantiomeric, or diastereomeric forms, or in mixtures thereof. Theprocesses for preparation can utilize racemates, enantiomers, ordiastereomers as starting materials. When diastereomeric or enantiomericproducts are prepared, they can be separated by conventional methods forexample, chromatographic or fractional crystallization. In addition, thecompounds of formula I may exist in tautomeric form. Such tautomericforms of the formula I are also contemplated herein as part of thepresent invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to inhibit MIP-1αor effective to treat or prevent inflammatory disorders.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Synthesis

Compounds of formula I may be prepared as shown in the followingreaction schemes and description thereof, as well as relevant literatureprocedures that may be used by one skilled in the art. Exemplaryreagents and procedures for these reactions appear hereinafter and inthe working Examples.

Scheme I describes a method for preparing compounds of formula IB (asubset of compounds of formula I). A ketone intermediate II can beobtained commercially, prepared by methods known in the literature or byother methods known to one skilled in the art. The reaction of ketone IIwith Meldrum's acid, commonly known as a Knoevenagel condensation, canbe carried out in anhydrous pyridine in the presence of a catalyticamount of piperidine (Baty, J. D., Jones, G., Moore, C., J. Org. Chem.,34:3295-3302 (1969)) or molecular sieves (Vogt, P. F., Molino, B. F.,Robichaud, A. J., Synth. Commun., 31:679-684 (2001)), or via dehydrativecondensation with TiCl₄ in CH₂Cl₂ (Brown, R. F. C., Coulston, K. J.,Eastwood, F. W., Gatehouse, B. M., Guddatt, L. W., Luke, W., Pfenninger,M., Rainbow, I., Aust. J. Chem., 37:2509-2524 (1984)). The disubstitutedMeldrum's acid alkylidene III can be purified by recrystallization fromalcohols such as ethanol or methanol, or via flash columnchromatography. The 1,4-conjugate addition of nucleophiles such alkyl oraryl Grignard's reagents (Haslego, M. L., Smith, F. X., Synth. Commun.,10:421-427 (1980)) or other organometallic reagents can be carried outin the presence or in the absence of Cu⁺ salts (such as CuBr, CuCN etc.)at room temperature or at 40° C. The isopropylidene malonate (IV) can beconverted to compounds IB via deprotection and subsequentdecarboxylation in wet organic solvent at 100 to 110° C. (J. Am. Chem.Soc., 125:6054-6055 (2003)). Alternatively, Knoevenagel condensation ofketone II with malononitrile in the presence of a wide range ofcatalysts such as NH₄OAc or amino acids provides alkylidene III-B, whichcan be easily purified by recrystallization and/or via flash columnchromatography. The 1,4-conjugate addition of nucleophiles such alkyl oraryl Grignard's reagents can be carried out in the absence of Cu⁺ saltsat 0° C. to room temperature to facilitate the adducts IV-B, which canbe easily converted to compounds IB via standard nitrile hydrolysis andsubsequent decarboxylation.

Scheme II describes a method for preparing compounds of formula IC (asubset of compounds of formula I) from compounds of formula IB. Thealcohol V, obtained from the reduction of IB, for example, with LAH ordiborane, can be converted to the corresponding mesylate or halide VI,followed by the subsequent elimination under basic condition to affordthe olefin VII. Upon oxidative cleavage of the C═C bond and furtheroxidation of the resulting aldehyde VIII, the compounds IC can beobtained.

Scheme III describes methods for preparing compounds of formula ID (asubset of compounds of formula IC, exemplified here where Z isadamantane or substituted adamantane). When Z is benzyl, substitutedbenzyl, or other heteroaryl methyl, the direct alkylation of the dianionof compound IX (generated for example with LiN(TMS)₂ or LDA) with thealkyl halide Z-X gives ID. Alternatively, compound ID can be synthesizedby converting compound I× to the corresponding ester IX-B, α-alkylationof IX-B to IX-C, followed by ester hydrolysis to provide compound ID.When Z is aryl, substituted aryl, heteroaryl or other aromatic groups,ketone X can be reacted with nucleophiles such as organolithium reagents(ZCH₂Li) or Grignard reagents (ZCH₂Mghalide) to afford the tertiaryalcohol XI, which can be converted to aldehyde XII via acid-catalyzedrearrangement. Further oxidation of aldehyde XII gives compounds ID.

Scheme IV describes a method for preparing compounds of formula IF andIF′ (subsets of compounds of formula I). Aldehyde VIII (see Scheme IIfor the synthesis) can be reacted with triethyl phosphoryl acetate togive α,β-unsaturated ester XIII, which may be subsequently converted toester XIV by metal-catalyzed hydrogenation (for example Pd/C or Pt inthe presence of H₂). Hydrolysis of the ester in basic condition givesthe carboxylic acid IF′. Alternatively, XIII may be hydrolyzed toprovide the corresponding acid IF directly.

There are numerous methods for the conversion of carboxylic acids toα-keto acids (see reviews: (a) Kovacs, L., Recl. Trav. Chim. Pays-Bas,112:471 (1993); (b) Cooper, A., Chem. Rev., 83:321 (1983)). Scheme Vexemplifies a method of using (cyanomethylene)phosphorane as a carbonylsynthon for preparing compounds of formula IG (a subset of compounds offormula I). Other methods known in the literature or known to oneskilled in the art can also be applied. The carboxylic acid XV (seeScheme I to IV) can be reacted with (cyanomethylene)triphenylphosphoranein the presence of coupling reagents such as EDCI to form cyano ketophosphoranes XVI, which can be oxidatively cleaved to form α-keto estersXVII. Further hydrolysis of ester XVII gives compounds IG (Wasserman,H., J. Org. Chem., 59:4364 (1994)).

Scheme VI describes a method for preparing compounds of formula IH (asubset of compounds of formula I). Ketone II reacts with Grignardreagent ZMgX or organolithium to give the tertiary alcohol XVIII. TheO-allylation with an allyl halide can be carried out in the presence ofbases such as NaH in reflux condition to give XIX, which can be furtherconverted to IH via oxidative cleavage of the C═C bond.

Scheme VII describes a method for preparing compounds of formula IJ,formula XX, and formula IK (subsets of compounds of formula I). Theenolate anions, obtained by treating carboxylic acid XV with bases suchas LDA/DMPU, can react with a variety of electrophilic hydroxylatingagents, such as oxygen (Wassermann, H. H. et al., Tetrahedron Lett.,1731 (1975)), molybdenum peroxide-pyridine-hexamethylphosphoramide(Vedejs, E., J. Am. Chem. Soc., 96:5944 (1974)), 2-sulfonyloxaziridine(Davis, F. A. et al., J. Org. Chem., 49:3243 (1984)), dibenzylperoxydicarbonate (Gore, M. P., Vederas, J. C., J. Org. Chem., 51:3700(1986)), and bis(trimethylsilyl)peroxide (TMSOOTMS) (Pohmakotr, M.,Winotai, C., Synthetic Communications, 18:2141-2146 (1988)) to formcompound IJ. On the other hand, the enolate anions can react withchloromethyl benzyl ether to give XX. Upon the cleavage of benzyl group,the acid IK can be obtained.

Scheme VIII describes a method for preparing compounds of formula IL(subset of compounds of formula I) from readily accessible material XXI(see Scheme I to III for the synthesis of XXI). Phenol XXII, obtainedfrom demethylation of XXI (when R═OMe) using BBr₃ or HBr in acetic acid,can be converted to the corresponding trifluoromethanesulphonate(triflate) or nonaflate XXIII by treatment with corresponding sulfonylhalide or sulphonic anhydride. Subsequent displacement of TfO or NfOwith —CN can be catalyzed by transition metals such as palladium(0) ornickel(0), yielding compound IL. Compound XXIII may also be useful forthe incorporating of a variety of R₄ groups via Pd or Ni catalyzedcoupling conditions well known in the literature. Alternatively, arylhalide XXI (when R=halo) can be converted to the corresponding nitrileIL through direct nucleophilic displacement catalyzed by transitionmetal such as Cu(I), Pd, Co, Ni (Ellis, G. P., Romney-Alexander, T. M.,Chem. Rev., 87:779-794 (1987), Arvela, R., Leadbeater, N. E., J. Org.Chem., 68:9122-9125 (2003)).

Scheme IX describes a method of preparing compounds of formula IM(subset of compounds of formula I). The alkylation of phenol XXII (seeScheme VIII) can be carried out in the presence of base such as NaH, toform XXIV. Upon the hydrolysis of the ester, IM can be obtained.

Scheme X describes a method for preparing compounds of formula IO(subset of compounds of formula I, when A represents adamantane). Theoxidation of compounds XXV (see Scheme I to III for synthesis) can becarried out under a wide variety of oxidative conditions such asdimethyldioxirane, potassium permanganate, ferrous iron-molecularoxygen, etc. The products and their yields are depended on the reactionconditions. These products can be separated by preparative HPLC, andtheir structures can be fully elucidated by 2D NMR technique.

Scheme XI describes a method of preparing compounds of formula IP(subset of compounds of formula I, when A represents adamantane).Compounds IP can be readily synthesized using Scheme I, II, and III.

Scheme XII describes a method of preparing compounds of formula IQa andIQb (subsets of compounds of formula I, when A represents adamantane).Ketone XXIX (see Scheme X and XI) reacts with reducing agents such asNaBH₄, LiBH₄, or reductases or other nucleophiles such as organomagnesium halides or organolithiums to form compounds IQa. On the otherhand, Ketone XXIX can react with TOSMIC under basic condition to affordIQb.

Scheme XIII describes a method for preparing compounds of formula IR(subset of compounds of formula I when Z represents adamantane).Compounds IP and IO (see Scheme IX for synthesis) can react with alkylhalides in the presence of a base such as NaH to form the O-alkylationproduct, which can be hydrolyzed to form compounds IR.

Scheme XIV describes a method of preparing compounds of formula IS (asubset of compound of formula I). The acids XXV (see Scheme I to III)can be converted to the corresponding acyl halides using a wide varietyof reagents such as thionyl chloride, sulfuryl chloride, oxalylchloride, and phosphorus trichloride, or alkyl or aryl chloroformate,etc. The acyl halide can react with ammonium hydroxide to form the amideXXX, which can be further converted to nitrile XXXI by treating withdehydration reagents such as acetic anhydride, acyl halide, POCl₃,chloroformate, etc. The nitrites XXXI can react with azide such assodium azide, Me₃SnN₃, etc to form the tetrazole IS.

Scheme XV describes a method of preparing compounds of formula IT (asubset of compounds of formula I). The acid XXV can readily react withamine HNR₉R₉ or its salt to form amide IT in the presence of a widevariety of peptide coupling reagents, such as carbodiimide type reagents(DCC, EDAC, DIC etc.), imidazolium type reagents (CDI, CBMIT, BOI, CMBIetc.), phosphonium type reagents (such as BOP, PyBOP etc.), uronium typereagents (HBTU, TBTU etc). Alternatively, the acid XXV can be convertedto acyl chloride XXXII, which reacts with amine HNR₉R₉ in the presenceof base such as i-Pr₂NEt, Et₃N to form compound IT.

Scheme XVI describes a method of preparing compounds of formula IU (asubset of compounds of formula I). The acid XXV can readily react withsulfonamide H₂NSO₂R₉ to form acyl sulfonamide IU in the presence of awide variety peptide coupling reagents, such as EDAC.

Scheme XVII describes a method of preparing compounds of formula IW (asubset of compounds of formula I). Exemplified in this scheme is thesynthesis of a variety of cyclic amines such as compounds XXXV, XXXVII,and XXXIX, but not limited to these structures. For example, when X″=O,XXXIII can react with isocyanate to form the corresponding carbamate.Alternatively, XXXIII can be converted to corresponding chloroformate byreacting with phosgene, then to carbamate by further reacting toappropriate amines. On the other hand, when X″=CO₂ (carboxylic acid),XXXV can be converted to heterocycles, such as oxazole, oxadiazole, etc.Alternatively, XXXV can be converted to nitrile, then to otherheterocycles such as tetrazole etc. Compound IW can be synthesized byreacting acid XXV with appropriate amines XXXV or XXXVII or XXXIX usingthe protocol described in Scheme XV.

EXAMPLES

The following working Examples serve to better illustrate, but notlimit, some of the preferred embodiments of the present invention.

General

The term HPLC refers to a Shimadzu high performance liquidchromatography with one of following methods:

Method A: Zorbax SB C18 4.6×75 mm column, Gradient solvent system: from50% A: 50% B to 0% A: 100% B (A=90% H₂O/10% MeOH+0.2% H₃PO₄); (B=90%MeOH/10% H₂O+0.2% H₃PO₄) for 8 min; with 2.5 mL/min flow rate and a 2min. hold, an ultra violet (UV) detector set at 220 nm.

Method B: Zorbax SB C18 4.6×75 mm column, Gradient solvent system: from100% A: 0% B to 0% A: 100% B (A=90% H₂O/10% MeOH+0.2% H₃PO₄); (B=90%MeOH/10% H₂O+0.2% H₃PO₄) for 8 min; with 2.5 mL/min flow rate and a 2min. hold, an ultra violet (UV) detector set at 220 nm.

Method C: Sunfire 3.5×150 mm column, Gradient solvent system: from 90%A: 10% B to 0% A: 100% B (A=95% H₂O/5% MeCN+0.05% TFA); (B=95% MeCN/5%H₂O+0.05% TFA) for 10 min, with 2.5 mL/min flow rate and a 5 min. hold,an ultra violet (UV) detector set at 220 nm.

The term Prep HPLC refers to an automated Shimadzu HPLC system using amixture of solvent A (10% MeOH/90% H₂O/0.2% TFA) and solvent B (90%MeOH/10% H₂O/0.2% TFA). The preparative columns were packed with YMC orPhenomenex Luna C18 5 micron resin or equivalent.

Abbreviations

The following abbreviations are employed in the Examples and elsewhereherein:

-   Ph=phenyl-   Bn=benzyl-   i-Bu=iso-butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   Bn=benzyl-   Bu=butyl-   Cbz=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl-   BOI=2-(1H-benzotriazol-1-yloxy)-4,5-dihydro-1,3-dimethyl-1H-Imidazolium-   BOP=2-(1H-Benzotriazol-1-yl)tris(dimethylamino)phosphonium    hexafluorophosphate-   CBMIT=1,1′-Carbonylbis(3-methylimidazolium)triflate-   CDI=1,1′-Carbonyldiimidazole-   CMBI=2-chloro-1,3-dimethyl-1H-benzimidazolium hexafluorophosphate-   DCC=1,3-Dicyclohexylcarbodiimide-   DCM=dichloromethane-   DEAD=Diethyl azodicarboxylate-   DIAD=Diisopropyl azodicarboxylate-   DIC=1,3-Diisopropylcarbodiimide-   DIEA=N,N-diisopropylethylamine-   DMA=N,N-dimethylacetylamide-   DMAP=4-(Dimethylamino)pyridine-   DMPU=N,N′-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone-   DMF=N,N-dimethylformamide-   DMSO=dimethylsulfoxide-   EtOAc=ethyl acetate-   EDC/EDCI/EDAC=3-ethyl-3′-(dimethylamino)propyl-carbodiimide    hydrochloride (or 1-[(3-(dimethyl)amino)propyl])-3-ethylcarbodiimide    hydrochloride)-   HBTU=1-[Bis(dimethylamino)methylene]-1H-benzotriazoliumhexa-fluorophosphate(1-)3-oxide-   HOAc or AcOH=acetic acid-   HOAT=1-hydroxy-7-azabenzotriazole-   HOBT=1-hydroxybenzotriazole-   HRMS=high resolution mass spectrum-   LAH=lithium aluminum hydride-   LDA=lithium diisopropylamide-   LiN(TMS)₂=lithium bis(trimethylsilyl)amide-   mCPBA=3-Chloroperoxybenzoic acid-   MsCl=Methanesulphonyl chloride-   Nf=Nonafluoro-1-butanesulfonyl-   Nf-F=Nonafluoro-1-butanesulfonyl fluoride-   NMP=N-Methylpyrrolidone-   NBS=N-Bromosuccinimide-   n-BuLi=n-butyllithium-   Pd/C=palladium on carbon-   PtO₂=platinum oxide-   PyBOP=benzotriazol-1-yloxytrispyrrolidino phosphonium    hexafluorophosphate-   SOCl₂=Thionyl chloride-   TBAF=tetrabutylammonium fluoride-   TBS=tert-Butyldimethylsilyl-   TBTU=O-Benzotriazolyl tetramethylisouronium tetrafluoroborate-   Tf=Trifluoromethanesulfonyl-   TMS=trimethylsilyl-   TEA=triethylamine-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   TOSMIC=Tosylmethyl isocyanide-   equiv=equivalent(s)-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=mole(s)-   mmol=millimole(s)-   meq=milliequivalent-   RT=room temperature-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   HPLC Rt=HPLC retention time-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS or Mass Spec=mass spectrometry-   NMR=nuclear magnetic resonance

Examples 1 and 2 2-(4′-Fluorophenyl)-tricyclo[3.3.1.13,7]decane-2-aceticacid and 2-(4′-Fluorophenyl)-tricyclo[3.3.1.13,7]dec-2-yl-propanedioicacid, Respectively

Compound 1A. 5-(2-Adamantylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione

This material is commercially available from the Aldrich Company. It canalso be synthesized using the following procedure: A solution of2-adamantanone (1.5 g, 10 mmol), Meldrum's acid (1.73 g, 12 mmol), and acatalytic amount of piperidine (5 drops) in anhydrous pyridine (10 mL)was stirred under argon for 5 days. After this time, the solution waspoured into ice water (30 mL), and the resulting mixture was stirred atroom temperature for 20 min. At the conclusion of this period, theresulting precipitate was collected by filtration and washed with coldwater (15 mL). The resulting solid was dried in vacuo to providecompound 1A (2.43 g, 88% yield) as a white solid.

Compound 1B.2,2-Dimethyl-5-(2-(4′-fluorophenyl)tricyclo[3.3.1.13,7]dec-2-yl)-1,3-dioxane-4,6-dione

To a suspension of copper(I)bromide (1.14 g, 7.947 mmol) in dry THF (10mL) at −2° C. under argon was added 4-fluorophenylmagnesium bromide (7.9mL, 15.9 mmol, 2.0 M in THF) dropwise. Upon completion of addition, theresulting mixture was stirred at −2° C. for 10 min, and then a solutionof compound 1A (0.732 g, 2.649 mmol) in THF (10 mL) was added through acannula. The reaction mixture was then allowed to warm to RT where itwas stirred under argon for about 16 hours. At the conclusion of thisperiod, the reaction mixture was quenched with NH₄Cl (saturated aqueoussolution, 20 mL) and then extracted with CH₂Cl₂ (3×30 mL). The combinedorganic layers were dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to provide a crude product. Thecrude product was purified via column chromatography (SiO₂, 10%EtOAc/n-Hexane) to provide compound 1B (0.75 g, 76% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.18-7.25 (m, 2H), 7.04 (t, J=8.79Hz, 2H), 4.29 (s, 1H), 2.97 (s, 2H), 2.38 (d, J=14.06 Hz, 2H), 2.04 (s,1H), 1.95 (d, J=13.18 Hz, 2H), 1.61-1.78 (m, 7H), 1.55 (s, 1H), 1.49 (s,3H), 0.77 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −115.28; ¹³C NMR (101MHz, CDCl₃) δ ppm 164.6, 129.1, 129.0, 115.5, 115.3, 105.2, 52.3, 51.3,38.3, 33.5, 33.2, 31.8, 30.6, 27.0, 26.7, 26.4; HPLC Rt (Method A): 7.38min.

Examples 1 and 2

A suspension of compound 1B (54.5 mg, 0.126 mmol) in a DMF-H₂O mixture(v/v 10:1) (1.3 mL) was heated at 100° C. under argon in an oil bath for6 h. After this time, the solvent was evaporated under reduced pressureto provide a residue. The residue was purified via Prep HPLC to yieldExamples 1 (25.3 mg, 60% yield) and 2 (9.7 mg, 20% yield). Example 1: ¹HNMR (400 MHz, CDCl₃) δ ppm 7.27-7.31 (m, 2H), 6.95-7.02 (m, 2H),2.69-2.73 (m, 2H), 2.54-2.61 (m, 2H), 2.20 (d, 2H), 1.91-1.99 (m, 1H),1.78-1.87 (m, 4H), 1.68-1.76 (m, 3H), 1.58 (d, 2H); ¹⁹F NMR (376 MHz,CDCl₃) δ ppm −117.16; HPLC Rt (Method A): 7.02 min; LC/MS (m/z)=287.3(M−H)⁻. Example 2: ¹H NMR (400 MHz, CDCl₃) δ ppm 7.18-7.25 (m, 2H),6.96-7.04 (m, 2H), 4.51-4.56 (m, 1H), 2.67-2.73 (m, 2H), 2.41 (d, 2H),2.04 (s, 1H), 1.91 (d, 2H), 1.81 (d, 2H), 1.69-1.76 (m, 3H), 1.59-1.67(m, 2H), 1.59 (none, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −115.14; HPLCRt (Method A): 6.18 min; LC/MS (m/z)=331.3 (M−H)⁻

In an alternate experiment, a suspension of compound 1B in a DMF-H₂Omixture was heated at 110° C. in an oil bath under argon for 12 h. Afterthis time, Example 1 was isolate in the manner described above in 80%yield.

Example 3 2-(4-Fluorophenyl)-2-adamantane carboxylic acid

Compound 3A

A solution of 2-admantanone (5.0 g, 33 mmol) in THF (25 mL) was stirredat 0° C. and 4-F-benzylmagnesium bromide (132 mL, 33 mmol) was addedslowly. Upon completion of addition, the reaction mixture was warmed toroom temperature where it was stirred for 16 hours. At the conclusion ofthis period, the reaction mixture was cooled at 0° C., quenched withsaturated NH₄Cl solution (30 mL), and extracted with Et₂O (3×30 mL). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated to provide compound 3A (8.0 g, 93%) as a yellow solid.LC/MS (m/z)=263 (M+H)⁺.

Compound 3B

To a stirred suspension of compound 3A (8.0 g, 30.7 mmol) in formic acid(32 mL) at 40° C. was added H₂O₂ (30% solution, 5.6 mL). Upon completionof addition, the reaction was heated at 40° C. in oil bath for about 16hours. After this time, the reaction mixture was allowed to cool to RT.Once at the prescribed temperature, the reaction mixture was poured intoice, stirred for 10 min, and then extracted with Et₂O (3×30 mL). Thecombined organic layers were washed with sat. NaHCO₃, dried over MgSO₄,and concentrated to yield a residue. The residue was purified via columnchromatography (SiO₂, 0-15% EtOAc in hexanes) to provide compound 3B(1.15 g, 14%) as a light yellow oil. LC/MS (m/z)=259 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ ppm 9.28 (s, 1H), 7.32 (dd, J=8.79, 5.27 Hz, 2H), 7.05 (t,J=8.57 Hz, 2H), 2.83 (s, 2H), 1.50-2.00 (m, 12H).

Example 3

To a solution of compound 3B (50 mg, 0.194 mmol) and 2-methyl-2-butene(2.0 mL) in a t-BuOH—H₂O mixture (2.3 mL, v/v 3:1) was added NaH₂PO₄(267.7 mg, 1.94 mmol), followed by sodium chlorite (131.6 mg, 1.16mmol). Upon completion of addition, the reaction mixture was stirred atRT for 3 h. After this time, Na₂SO₃ (aq.) was added to quench thereaction, and the resulting mixture was extracted with EtOAc (3×5 mL).The combined organic layers were dried over MgSO₄, filtered, and thenconcentrate to yield a crude product. The crude product was purified viaPrep HPLC to provide Example 3 (21.2 mg, 40%). HPLC Rt (Method A): 6.686min; HRMS (high resolution mass spectrum): Calculated for C₁₇H₁₈O₂F:273.1291, found: 273.1298. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.42-7.49 (m,2H), 6.98-7.07 (m, 2H), 2.91 (br. s., 2H), 2.03 (d, J=12.3 Hz, 2H),1.82-1.94 (m, 3H), 1.65-1.79 (m, 6H), 1.59 (d, 2H). ¹⁹F NMR (376 MHz,CDCl₃) δ ppm −115.67 (s).

Example 4

Compound 4A

To a suspension of NaH (86 mg, 2.15 mmol) in THF (2 mL) was addedtriethyl phosphonoacetate (481 mg, 2.15 mmol) dropwise. Upon completionof addition, the mixture was stirred at RT for 1 h and then a solutionof compound 3B (170 mg, 0.65 mmol, see Example 3) in THF (1.5 mL) wasadded dropwise. The reaction mixture was stirred at RT for about 16hours and then the solvent was evaporated to dryness to yield a residue.The residue was purified via column chromatography (SiO₂, 0-10% EtOAc inhexanes) to provide compound 4A (100 mg, 46%) as a colorless oil. LC/MS(m/z)=329 (M+H)⁺.

Compound 4B

To a solution of compound 4A (60 mg, 0.18 mmol) in MeOH (2.0 mL) wasadded Pd/C catalyst (12 mg, 20%). Upon completion of addition, thereaction mixture was charged with a H₂ balloon for about 16 hours. Afterthis time, the Pd/C catalyst was filtered off, and the filter cake wasrinsed with MeOH. The solvent was evaporated to provide compound 4B (60mg, 100%) as a colorless oil. LC/MS (m/z)=331 (M+H)⁺.

Example 4

To a solution of compound 4B (60 mg, 0.18 mmol) in THF (1.0 mL) wasadded saturated LiOH (1.0 mL, aqueous). Upon completion of addition, thereaction mixture was stirred at room temperature for three days duringwhich time a few drops of MeOH were added. At the conclusion of thethree day period, the reaction mixture was acidified with 1N HCl topH=2. Once at the prescribed pH, the resulting mixture was extractedwith EtOAc (3×5 mL). The combined organic layers were evaporated todryness to yield a residue. The residue was purified via Prep HPLC toprovide Example 4 (5.8 mg, 10% yield) as white solid. LC/MS (m/z)=301(M−H)⁻. HPLC Rt (Method A): 7.62 min; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.15(dd, J=8.35, 5.71 Hz, 2H), 6.93 (t, J=8.35 Hz, 2H), 2.23 (s, 2H), 2.14(d, J=12.30 Hz, 2H), 1.89-1.97 (m, 2H), 1.79-1.89 (m, 3H), 1.58-1.77 (m,7H), 1.49 (d, J=12.74 Hz, 2H).

Example 5 2-Benzyl-2-adamantane carboxylic acid

To a stirred solution of 2-adamantane carboxylic acid (114.5 mg, 0.635mmol) in dry THF (6 mL) at −40° C. under argon was slowly added LDA(0.79 mL, 1.588 mmol), followed by DMPU (93 μL, 0.688 mmol). Uponcompletion of addition, the mixture was gradually warmed to RT, where itstirred for 1 hour. After this time, the reaction mixture was cooled to0° C., and benzyl bromide (83 μL, 0.699 mmol) was added. The resultingmixture was warmed to RT over a 2 hour period. Once at the prescribedtemperature, aqueous HCl (1 mL, 1 N) was added to quench the reaction.The reaction mixture was extracted with EtOAc (3×5 mL), and the combinedorganic layers were dried (Na₂SO₄) and then concentrated to afford acrude product. The crude product was purified via column chromatography(SiO₂, 2% MeOH in CH₂Cl₂, with 0.1% HOAc) to afford a less crudeproduct. This less crude product was further purified via Prep HPLC toprovide Example 5 (29 mg, 17% yield) as a white solid. HPLC Rt (MethodA): 7.301 min; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.17-7.26 (m, 3H),7.09-7.15 (m, 2H), 3.08 (s, 2H), 2.27 (d, J=11.9 Hz, 2H), 2.14 (s, 2H),1.83-1.98 (m, 4H), 1.69-1.79 (m, 6H).

Example 62-(4-Fluorophenyl)-tricyclo[3.3.1.13,7]decane-2-hydroxymethyl-2-aceticacid

Compound 6A.2-(4-Fluorophenyl)-tricyclo[3.3.1.13,7]decane-2-benzyloxy-2-acetic acid

To a solution of Example 2 (33 mg, 0.114 mmol) in dry THF (1 mL) at −40°C. under argon was slowly added LDA (0.13 mL, 0.267 mmol), followed byDMPU (15.3 μL, 0.124 mmol). Upon completion of addition, the reactionmixture was gradually warmed to RT, where it stirred for 1 hour. At theconclusion of this period, the reaction mixture was cooled to 0° C., andbenzyl chloromethyl ether (17.2 mL, 0.124 mmol) was added. The resultingmixture was warmed to RT in 2 hours and then aqueous HCl (1 mL, 1 N) wasadded to quench the reaction. The resulting mixture was extracted withEtOAc (3×5 mL). The combined organic layers were washed with 1 N HCl,brine, dried over Na₂SO₄ and concentrated to yield a crude product. Thecrude product was purified via Prep HPLC to afford compound 6A (15 mg,32% yield) as a white solid. HRMS (high resolution mass spectrum):Calculated for C₂₆H₃₀O₃F: 409.2179, found: 409.2176. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.22-7.40 (m, 5H), 7.02-7.17 (m, 2H), 6.80-7.01 (m, 2H),4.33-4.50 (m, 2H), 3.73 (dd, J=10.1, 3.5 Hz, 1H), 3.67 (dd, J=9.0, 3.7Hz, 1H), 3.18-3.30 (m, 1H), 2.42-2.66 (m, 3H), 2.19 (d, J=12.3 Hz, 1H),1.98 (br. s., 1H), 1.63-1.88 (m, 7H), 1.45-1.62 (m, 2H).

Example 6

Under argon, to a solution of compound 6A (12 mg, 0.029 mmol) in EtOH(0.5 mL) was added 10% Pd/C catalyst (5 mg). Upon completion ofaddition, the reaction mixture was charged with H₂ balloon for 2 h.After this time, the Pd/C catalyst was filtered off, and the filter cakewas rinsed with EtOH. The filtrate was concentrated under reducedpressure to afford a crude product. The crude product was purified viaPrep HPLC to afford Example 6 (3.2 mg, 34% yield) as white solid. HPLCRt (Method A): 5.935 min; LC/MS (m/z)=319 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.07-7.17 (m, 1H), 6.99-7.07 (m, 1H), 6.81-6.95 (m, 2H),3.52-3.70 (m, 4H), 3.48 (dd, J=10.8, 3.3 Hz, 1H), 3.24-3.39 (m, 2H),2.64 (br. s., 1H), 2.50 (br. s., 1H), 2.38 (br. s., 1H), 2.11 (br. s.,1H), 1.91 (br. s., 1H), 1.54-1.80 (m, 5H), 1.46 (d, 2H).

Example 7

Compound 7A

To a solution of Example 1 (100 mg, 0.35 mmol),(Triphenylphosphoranylidene)acetonitrile (137 mg, 0.45 mmol), and DMAP(55 mg, 0.45 mmol) in CH₂Cl₂ (4.0 mL) was added EDC (86 mg, 0.45 mmol).Upon completion of addition, the reaction mixture was stirred at RT forabout 16 hours. After this time, the solvent was removed under reducedpressure to yield a residue. The residue was purified via columnchromatography (SiO₂, 0-30% EtOAc in hexanes) to provide compound 7A(200 mg, 100%) as a colorless oil. LC/MS (m/z)=572 (M+H)⁺.

Compound 7B

To a solution of Compound 7A (200 mg, 0.35 mmol) in a CH₂Cl₂/MeOH (3.5mL/1.5 mL) mixture at −78° C. was bubbled O₃ gas until a light bluecolor appeared (about 10 min). Once at the prescribed color, thereaction mixture was aspirated with argon gas for about 10 min to removeany excess O₃ and then a few drops of Me₂S were added. Upon completionof addition, the reaction mixture was warmed to RT. Once at theprescribed temperature, the solvent was evaporated to yield a residue.The residue was purified via column chromatography (SiO₂, 0-15% EtOAc inhexanes) to provide compound 7B (90 mg, 77%) as a white solid. LC/MS(m/z)=331 (M+H)⁺.

Example 7

To a solution of compound 7B (30 mg, 0.09 mmol) in THF (1.0 mL) wasadded a saturated LiOH solution (1.0 mL, aqueous). Upon completion ofaddition, the reaction mixture was stirred at room temperature for about16 hours. At the conclusion of this period, the reaction mixture wasacidified with 1 N HCl to a pH of less than 5. Once at the prescribedpH, the reaction mixture was extracted with CH₂Cl₂ (3×5 mL). Thecombined organic layers were dried over MgSO₄ and concentrated to yielda crude product. The crude product was purified via Prep HPLC to provideExample 7 (14.4 mg, 50% yield) as a white solid. LC/MS (m/z)=315 (M−H)⁻.HPLC Rt (Method A): 6.85 min; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.23 (dd,J=9.23, 5.27 Hz, 2H), 6.96 (t, J=8.57 Hz, 2H), 3.35 (s, 2H), 2.57 (s,2H), 2.21 (d, J=11.86 Hz, 2H), 1.98 (s, 1H), 1.77-1.92 (m, 4H), 1.71 (s,3H), 1.58 (m, 2H).

Example 8

Compound 8A. 2-(4-Fluorophenyl)-2-adamantanol

To a solution of 2-adamantanone (1.214 g, 8.081 mmol) in THF (10 mL) atRT was slowly added 4-fluorophenyl magnesium bromide (4.45 mL, 8.89mmol, 2.0 M in Et₂O). The reaction mixture was heated to 65° C., whereit stirred for 1 h. After this time, the reaction mixture was cooled toRT, quenched with NH₄Cl (saturated aqueous solution, 10 mL), and thenextracted with Et₂O (2×20 mL). The combined organic layers were washedwith H₂O and brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to yield compound 8A (1.59 g, 80%)as a lightly yellow solid.

Compound 8B. 2-Allyloxy-2-(4-fluorophenyl)-tricyclo[3.3.1.13,7]decane

A suspension of NaH (44 mg, 1.741 mmol, 95%) and compound 8A (306 mg,1.244 mmol) in THF (6 mL) was heated to 65° C. for 30 min. After thistime, the reaction mixture was cooled to RT, and allyl bromide (0.155mL, 1.74 mmol) was added. Upon completion of addition, the resultingmixture was heated at reflux for 2 h. At the conclusion of this period,the reaction mixture was analyzed by HPLC, which showed that thereaction was complete. The reaction mixture was cooled to RT, quenchedwith dilute HCl (aq.), and then extracted with CH₂Cl₂ (3×10 mL). Thecombined organic layers were washed with H₂O and brine and then driedover Na₂SO₄. The solvent was evaporated to afford a crude product. Thecrude product was purified via column chromatography (SiO₂, 5% EtOAc inHexanes) to afford compound 8B (0.217 g, 61% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 7.39-7.50 (m, 2H), 6.96-7.08 (m, 2H), 5.61-5.79 (m, 1H),4.90-5.20 (m, 2H), 3.40 (dd, J=3.5, 1.5 Hz, 2H), 2.60 (s, 2H), 2.37 (d,J=10.9 Hz, 2H), 1.88 (s, J=2.8 Hz, 1H), 1.59-1.80 (m, 9H); ¹⁹F NMR (376MHz, CDCl₃) δ ppm −116.01.

Compound 8C

Ozone (ca. 5% in O₂) was bubbled into a well-stirred solution ofcompound 8B (0.217 g, 0.757 mmol) in CH₂Cl₂ (7.5 mL) at −78° C. After apale blue color appeared, the gas flow was stopped and Me₂S (6 drops)was added. The reaction mixture was allowed to warm to RT, where itstirred for 3 h. After this time, the solvent was removed under reducedvacuum to yield a residue. The residue was purified via columnchromatography (SiO₂, 5% EtOAc in n-hexane) to provide compound 8C (46mg, 21% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 9.42 (s, 1H), 7.37-7.57(m, 2H), 6.94-7.14 (m, 2H), 3.53 (d, J=1.0 Hz, 2H), 2.61 (s, 2H), 2.33(d, J=11.9 Hz, 2H), 1.91 (d, J=2.5 Hz, 1H), 1.57-1.82 (m, 9H); ¹⁹F NMR(376 MHz, CDCl₃) δ ppm −114.84.

Example 8

Example 8 was prepared in a similar manner as described in Example 4,utilizing compound 8C and the other appropriate reagents. ¹H NMR (400MHz, CDCl₃) δ ppm 7.38-7.49 (m, 2H), 6.97-7.16 (m, 2H), 3.59 (s, 2H),2.63 (s, 2H), 2.23 (s, 2H), 1.94 (s, 1H), 1.56-1.84 (m, 10H); HRMS(ESI): Calculated for C₁₈H₂₀O₃F: 303.1396, found: 303.1401.

Example 9 2-(3′-Cyanophenyl)-tricyclo[3.3.1.13,7]decane-2-acetic acid

Compound 9A. 2-(3′-Hydroxyphenyl)-tricyclo[3.3.1.13,7]decane-2-aceticacid

To a solution of2-(3′-methoxyphenyl)-tricyclo[3.3.1.13,7]decane-2-acetic acid (199 mg,0.667 mmol, as prepared following the procedure described in Example 1)in CH₂Cl₂ (5 mL) at −78° C. under argon was added BBr₃ (1.33 mL, 1.33mmol, 1 M solution in CH₂Cl₂). The mixture was carefully warmed to RT,and then stirred at RT for 2 h. Upon completion of this period, thereaction mixture was quenched with saturated NaHCO₃ (aq. 1 mL) and thenthe solvent was evaporated to dryness to provide a residue. The residuewas purified via Prep HPLC to provide compound 9A (152.7 mg, 80% yield)as a white solid. HPLC Rt (Method A): 5.480 min; ¹H NMR (400 MHz, CDCl₃)δ ppm 7.11 (t, J=7.9 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.74-6.80 (m, 1H),6.60 (dd, J=7.9, 1.8 Hz, 1H), 3.04 (br. 1H), 2.37-2.65 (m, J=31.2 Hz,3H), 2.14 (s, 2H), 1.83-1.96 (m, 3H), 1.77 (d, J=13.6 Hz, 3H), 1.62-1.72(m, 4H), 1.53 (d, J=12.3 Hz, 2H).

Compound 9B

To a solution of compound 9A (30 mg, 0.105 mmol) in DMF (1.2 mL) at −10°C. was added Et₃N (45 μL, 0.325 mmol) followed by Nf-F (40 μL, 0.2199mmol). Upon completion of addition, the reaction mixture was warmed toRT, where it stirred for 3 h. After this time, the solvent wasevaporated to provide a residue. The residue was purified via Prep HPLCto afford compound 9B (51 mg, 86% yield) as a white solid. LC/MS(m/z)=567.0 (M−H)⁻.

Example 9

To a solution of compound 9B (51 mg, 0.09 mmol) and Zn(CN)₂ (21.1 mg,0.18 mmol) in anhydrous DMF (2 mL) under argon was added Pd(PPh₃)₄ (20.8mg, 0.018 mmol). Upon completion of addition, the reaction mixture wasstirred in an 85° C. oil bath for 8 h. At the conclusion of this period,the solvent was removed under reduced pressure to provide a residue. Theresidue was purified via Prep HPLC to afford Example 9 (7.3 mg, 27%yield) as a white solid. HPLC Rt (Method A): 6.023 min; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.62 (s, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.46-7.52 (m, 1H),7.41 (t, J=7.7 Hz, 1H), 2.73 (s, 2H), 2.58 (s, 2H), 2.21 (d, J=13.6 Hz,2H), 1.99 (s, 1H), 1.85 (d, J=13.6 Hz, 2H), 1.67-1.79 (m, 5H), 1.54-1.67(m, 2H).

Example 10

A mixture of compound 9A (24 mg, 0.084 mmol), K₂CO₃ (24.8 mg, 0.251mmol), and ethyl iodoacetate (20 μL, 0.168 mmol) in THF (1 mL) wasrefluxed under argon for 3 h. At the conclusion of this period, thereaction mixture was cooled to RT, neutralized with 1 N HCl (aq.) to apH=3, and then extracted with EtOAc (3×5 mL). The combined organiclayers were evaporated to dryness and then THF (1 mL) and saturated LiOH(aq., 0.5 mL) were added. The resulting mixture was heat to 70° C.,where it stirred for about 16 h. After this time, the mixture wasneutralized with 1 N HCl (aq.) to a pH=1, and then extracted with EtOAc(3×5 mL). The combined organic layers were evaporated to dryness toyield a residue. The residue was purified via Prep HPLC to provideExample 10 (7.8 mg, 27% yield). HPLC Rt (Method A): 5.703 min; HRMS(ESI): Calculated for C₂₀H₂₃O₅: 343.1545, found: 343.1540; ¹H NMR (400MHz, CD₃OD) δ ppm 7.22 (t, J=8.1 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.96(s, 1H), 6.74 (dd, J=8.2, 1.9 Hz, 1H), 4.61 (s, 2H), 2.56-2.76 (m, 4H),2.30 (d, J=13.4 Hz, 2H), 1.93 (s, 3H), 1.84 (d, J=13.4 Hz, 2H), 1.75 (s,2H), 1.69 (s, 1H), 1.61 (d, J=12.4 Hz, 2H).

Examples 11 to 16

To a solution of potassium hydroxide (106.6 mg, 1.618 mmol) in water(3.2 mL) was added KMnO₄ (290 mg, 1.78 mmol). The resulting solution waswarmed in an oil bath (about. 50° C.) and then Example 1 (460 mg, 1.618mmol) was added portionwise. After the addition was complete, thereaction mixture was allowed to warm to a gentle reflux, where itstirred until all of the KMnO₄ was consumed (about 1.5 h). Once theKMnO₄ was completely consumed, the reaction mixture was cooled to RT,and then acidified with 6 N HCl (aq.). Sodium metabisulfite was added toremove MnO₂ (until all the brown color became white). The resultingsolid was collected by filtration and then subjected to Prep HPLC toprovide Examples 11 to 16. Some Example 1 starting material was alsorecovered (260 mg, white solid).

Example 11 (45.6 mg, white solid, 21.6% yield based on the recovery ofstarting material). HPLC Rt (Method B): 5.933 min; HRMS (ESI):Calculated for C₁₈H₂₀O₃F: 303.1396, found: 303.1401; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.28-7.38 (m, 2H), 7.00 (t, J=8.8 Hz, 2H), 2.84 (br. s.,2H), 2.66 (s, 2H), 2.08-2.29 (m, 4H), 1.80 (d, J=11.9 Hz, 2H), 1.63-1.74(m, 4H), 1.53 (d, 2H). ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −117.60.

Example 12 (70.5 mg, white solid, 33.4% yield based on the recovery ofstarting material). HPLC Rt (Method B): 6.986 min; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.56 (br. s., 1H), 7.34 (dd, J=8.6, 5.6 Hz, 2H), 7.09(t, J=8.8 Hz, 2H), 3.31 (br. s, 3H), 2.75 (br. s, 2H), 2.43-2.63 (m,2H), 2.09 (d, J=12.4 Hz, 2H), 1.87 (br. s., 1H), 1.46-1.68 (m, 2H), 1.36(d, J=12.6 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −118.4; HRMS (ESI):Calculated for C₁₈H₂₀O₃F: 303.1396, found: 303.1396.

Example 13 (10 mg, white solid, 4.7% yield based on the recovery ofstarting material). HPLC Rt (Method B): 6.638 min; HRMS (ESI):Calculated for C₁₈H₁₈O₃F: 301.1240, found: 301.1241; ¹H NMR (500 MHz,CD₃OD) δ ppm 7.39 (dd, J=9.1, 5.2 Hz, 2H), 6.98 (t, J=8.8 Hz, 2H), 3.55(br. s., 1H), 3.23 (d, J=13.7 Hz, 1H), 2.61-2.70 (m, 2H), 2.55 (br. s.,1H), 2.39-2.48 (m, 1H), 2.27 (br. s., 1H), 2.08-2.17 (m, J=12.6, 3.2,3.2, 3.0 Hz, 1H), 1.96-2.06 (m, 2H), 1.89-1.96 (m, 2H), 1.78-1.86 (m,1H), 1.67-1.75 (m, 1H).

Example 14 (15 mg, white solid, 7.1% yield based on the recovery ofstarting material). HRMS (ESI): Calculated for C₁₈H₁₈O₃F: 301.1240,found: 301.1231.

Example 15 (15 mg, white solid, 7.1% yield based on the recovery ofstarting material). HPLC Rt (Method B): 7.665 min; LC/MS (m/z)=303.2(M−H)⁻; HRMS (ESI): Calculated for C₁₈H₂₀O₃F: 303.1396, found: 303.1391;¹H NMR (500 MHz, CD₃OD) δ ppm 7.81-8.01 (m, 2H), 6.95 (t, J=9.1 Hz, 2H),3.25 (d, J=14.3 Hz, 1H), 2.77 (d, J=14.3 Hz, 2H), 2.29-2.39 (m, 2H),2.09-2.20 (m, 2H), 1.91-1.98 (m, 1H), 1.63-1.74 (m, 5H), 1.61 (d, J=12.1Hz, 1H), 1.45 (dd, J=12.9, 2.5 Hz, 1H).

Example 16 (3 mg, white solid) LC/MS (m/z)=319.3 (M−H)⁻.

Example 17

To a suspension of NaH (21 mg, 0.831 mmol, 95%) in anhydrous THF (2 mL)was added Example 12 (25.8 mg, 0.085 mmol). Upon completion of addition,the reaction mixture was heated to reflux under argon where it stirredfor 1 h and then iodomethane was added (0.1 mL). Upon completion ofaddition, the resulting mixture was heated at reflux for about 16 h.After this time, the solvent was removed under reduced pressure to yielda residue. The residue was dissolved in THF (1 mL) and saturated LiOH(0.5 mL, aqueous). The resulting mixture was heated to 67° C., where itstirred for about 16 h. At the conclusion of this period, the mixturewas cooled to RT, acidified with 1 N HCl to pH=1, and then extractedwith a EtOAc-MeOH solution (8:2, v/v) (5×5 mL). The combined organiclayers were evaporated to dryness to yield a residue. The residue waspurified via Prep HPLC to provide Example 17 (15.2 mg, 56% yield) as awhite solid. HPLC Rt (Method B): 7.753 min; HRMS (ESI): Calculated forC₁₉H₂₂O₃F: 317.1553, found: 317.1541; 1H NMR (400 MHz, CDCl3) δ ppm7.26-7.39 (m, 2H), 6.99 (t, J=8.7 Hz, 2H), 3.29 (s, 3H), 2.86 (s, 2H),2.67 (s, 2H), 2.21 (d, J=12.4 Hz, 2H), 2.03 (s, 1H), 1.69-1.87 (m, 6H),1.45 (d, J=12.9 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ ppm −118.23.

Example 18

To a stirred solution of Example 13 (14.4 mg, 0.047 mmol) in dry THF(1.0 mL) at RT under argon was added methyl magnesium bromide (0.4 mL,0.56 mmol, 1.4 M in THF). Upon completion of addition, the reactionmixture was heated to 65° C., where it stirred for 1 h. After this time,the solvent was removed under reduced pressure to yield a residue. Theresidue was purified via Prep HPLC to provide Example 18 (7.2 mg, 48%yield) as a white solid. HPLC Rt (Method B): 7.00 min; HRMS (ESI):Calculated for C₁₉H₂₂O₃F: 317.1553, found: 317.1544; ¹H NMR (400 MHz,CD₃OD) δ ppm 7.41-7.56 (m, 1H), 7.19-7.32 (m, 1H), 6.83-7.04 (m, 2H),3.11 (d, J=13.6 Hz, 1H), 2.76-2.91 (m, 1H), 2.39-2.52 (m, 3H), 2.32 (d,J=13.6 Hz, 1H), 2.19 (dd, J=14.3, 2.7 Hz, 1H), 1.81-2.03 (m, 3H),1.70-1.81 (m, 2H), 1.57-1.67 (m, 1H), 1.51 (s, 1H), 1.35 (s, 3H).

Example 19 2-(4-Fluorophenyl)-2-(1H-tetrazol-5-ylmethyl)adamantine

Compound 19A. 2-(4-Fluorophenyl)-tricyclo[3.3.1.13,7]decane-2-acetamide

To a stirred solution of Example 1 (120 mg, 0.42 mmol) in CH₂Cl₂ (2 mL)at 0° C. was added triethylamine (71 μL, 0.5 mmol), followed by i-butylchlorformate (57 μL, 0.44 mmol). Upon completion of addition, thereaction mixture was stirred at 0° C. for 45 min. At the conclusion ofthis period, NH₄OH (2.0 mL) was added, and the resulting mixture waswarmed to RT where it stirred for about 16 hours. After this time, waterwas added, and the resulting mixture was extracted with CH₂Cl₂ (3×5 mL).The combined organic layers were dried over MgSO₄ and concentrated toprovide compound 19A (150 mg, 100%) as a light yellow solid. LC/MS(m/z)=288 (M+H)⁺. ¹H NMR (400 MHz, CD₃CN) δ ppm 7.26-7.38 (m, 2H),6.94-7.07 (m, 2H), 5.14-5.40 (m, 2H), 2.58 (br. s., 2H), 2.51 (s, 2H),2.26 (d, J=11.4 Hz, 2H), 1.85-1.95 (m, 1H), 1.76 (d, J=13.6 Hz, 4H),1.63-1.71 (m, 3H), 1.56 (d, 2H). ¹⁹F NMR (376 MHz, Solvent) δ ppm−121.40.

Compound 19B

To a stirred solution of compound 19A (150 mg, 0.4 mmol) in pyridine(2.5 mL) was slowly added MsCl (316 μL, 4.0 mmol). Upon completion ofaddition, the reaction mixture was stirred at room temperature for about16 h. After this time, the reaction mixture was quenched with water (1mL), and then extracted with EtOAc (3×5 mL). The combined organic layerswere washed with water, dried over MgSO₄, and concentrated to yield aresidue. The residue was purified via column chromatography (SiO₂, 0-10%EtOAc in hexanes) to afford compound 19B (90 mg, 83%) as a white solid.LC/MS (m/z)=270 (M+H)⁺.

Example 19

To a stirred solution of compound 19B (80 mg, 0.29 mmol) in toluene (3.0mL) was added azidotrimethyltin (103 mg, 0.49 mmol). Upon completion ofaddition, the resulting mixture was heated to 100° C. where it stirredfor 18 hr. After this time, the solvent was removed under reducedpressure to yield a residue. The residue was purified via Prep HPLC toafford Example 19 (7.6 mg, 8.3% yield) as a white solid. LC/MS (m/z)=313(M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ ppm 6.98-7.05 (m, 2H), 6.95 (t, J=9.0Hz, 2H), 2.45-2.56 (m, 4H), 2.09-2.24 (m, 5H), 2.02 (br. s., 1H), 1.74(d, J=19.8 Hz, 5H), 1.59-1.67 (m, 2H). ¹⁹F NMR (376 MHz, CD₃OD) δ ppm−118.87 (s).

Example 20 2-(4-Fluorophenyl)-2-(1H-tetrazol-5-yl)adamantane

Compound 20A

A mixture of compound 3B (400 mg, 1.55 mmol), sodium acetate (500 mg),and hydroxylamine hydrochloride (400 mg) in acetic acid (45 mL) washeated at 50° C. for 2 h. After this time, the reaction mixture wasallowed to cool to RT, where it stirred for about 16 hours. At theconclusion of this period, the solvent was evaporated under reducedpressure to yield a residue. The residue was dissolved in water (3 mL)and then extracted with CH₂Cl₂ (3×5 mL). The combined organic layerswere washed (saturated NaHCO₃ aqueous solution), dried over MgSO₄, andconcentrated to yield compound 20A (360 mg, 85% yield) as a lightlyyellow oil. LC/MS (m/z)=274 (M+H)⁺.

Compound 20B. 2-(4-Fluorophenyl)-2-cyanoadamantane

A stirred solution of compound 20A (360 mg, 1.3 mmol) in aceticanhydride (8.0 mL) was heated at reflux for 1 h. At the conclusion ofthis period, the reaction mixture was allowed to cool to RT, where itstirred for about 16 hours. After this time, MeOH (8 mL) and a few dropsof concentrated H₂SO₄ were added to the reaction mixture. The resultingmixture was diluted with H₂O (20 mL) and extracted with Et₂O (3×10 mL).The combined organic layers were dried over MgSO₄ and concentrated toyield a residue. The residue was purified via column chromatography(SiO₂, 0-10% EtOAc in hexanes) to yield compound 20B (110 mg, 33%) as alightly yellow oil. LC/MS (m/z)=256 (M+H)⁺.

Example 20

A mixture of compound 20B (110 mg, 0.43 mmol) and azidotrimethyltin (205mg, 0.86 mmol) in toluene (3.0 mL) was heated at 100° C. for 2 days. Atthe conclusion of this period, the solvent was removed under reducedpressure to yield a residue. The residue was purified via Prep HPLC toprovide Example 20 (10 mg, 7.8% yield) as a white solid. LC/MS (m/z)=299(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.53 (dd, J=9.0, 5.1 Hz, 2H), 6.98(t, J=8.6 Hz, 2H), 3.32 (br. s., 2H), 2.01 (d, J=12.7 Hz, 2H), 1.81-1.97(m, 6H), 1.76 (br. s., 4H). ¹³C NMR (101 MHz, CDCl₃) δ ppm 163.21,160.75, 134.45, 128.34, 128.26, 123.66, 116.15, 115.93, 45.43, 37.18,34.94, 33.33, 31.13, 26.79, 26.27.

Example 21

To a stirred suspension of Example 1 (30 mg, 0.1 mmol), EDAC (28 mg,0.15 mmol), HOBT (20 mg, 0.15 mmol), and 3-hydroxyazetidinehydrochloride (16 mg, 0.15 mmol) in CH₂Cl₂ (1.5 mL) was addedN,N-diisopropylethylamine (20 mg, 0.15 mmol). Upon completion ofaddition, the reaction mixture was stirred at RT for about 16 hours, andthen the solvent was removed under reduced pressure to yield a residue.The residue was purified via Prep HPLC to provide Example 21 (15 mg, 43%yield) as a white solid. LC/MS (m/z)=344 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃)δ ppm 7.36 (dd, J=9.1, 5.2 Hz, 2H), 6.97-7.12 (m, 2H), 4.10-4.23 (m,1H), 3.92 (dd, J=11.5, 6.0 Hz, 1H), 3.49 (dd, J=10.7, 4.1 Hz, 1H),3.22-3.33 (m, 1H), 2.91 (dd, J=9.1, 4.1 Hz, 1H), 2.64 (br. s., 2H),2.36-2.50 (m, 2H), 2.32 (d, J=12.6 Hz, 2H), 1.97 (br. s., 1H), 1.82 (t,J=12.1 Hz, 2H), 1.64-1.75 (m, 2H), 1.50-1.63 (m, 1H).

Example 22

Example 1 (50 mg, 0.17 mmol), EDCI (42 mg, 0.22 mmol), DMAP (27 mg, 0.22mmol), and methanesulfonamide (21 mg, 0.22 mmol) were dissolved inCH₂Cl₂ (1.5 mL). The resulting mixture was stirred at RT for about 16 h.After this time, the solvent was evaporated under reduced pressure toprovide a residue. The residue was purified via PrepHPLC to provideExample 22 as a white solid (54 mg, 67% yield). LC/MS (m/z)=366 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ ppm 7.30 (dd, J=9.01, 5.49 Hz, 2H), 7.17 (s,1H), 7.04 (t, J=8.57 Hz, 2H), 2.93 (s, 3H), 2.62 (s, 2H), 2.43-2.57 (m,2H), 2.09-2.29 (m, 2H), 1.90-2.02 (m, 1H), 1.49-1.89 (m, 9H).

Example 232-(9-(4-Fluorophenyl)-3-hydroxybicyclo[3.3.1]nonan-9-yl)-1-(3-hydroxyazetidine-1-yl)ethanone

Compound 23A.2,2-Dimethyl-5-(3-methylenebicyclo[3.3.1]nonan-9-ylidene)-1,3-dioxane-4,6-dione

Compound 23A can be prepared from 3-methylenebicyclo[3.3.1]nonan-9-one(reference: Buono, F., Tenaglia, A., J. Org. Chem., 65:3869-3874 (2000))and Meldrum's acid by following the procedure in Example 1 and 2. ¹H NMR(400 MHz, CDCl₃) δ ppm 4.82 (t, J=2.1 Hz, 2H), 4.06 (s, 2H), 2.56-2.77(m, 4H), 2.33-2.55 (m, 1H), 1.98-2.14 (m, 2H), 1.80-1.95 (m, 2H), 1.77(s, 3H), 1.80 (s, 3H), 1.29-1.40 (m, 1H).

Compound 23B.5-(9-(4-Fluorophenyl)-3-methylenebicyclo[3.3.1]nonan-9-yl)-2,2-dimethyl-1,3-dioxane-4,6-dioneand its Regioisomer

To a suspension of copper(I)bromide (0.416 g, 2.90 mmol) in dry THF (15mL) at −2° C. under argon was added 4-fluorophenylmagnesium bromide (6.4mL, 6.37 mmol, 1.0 M in THF) dropwise. Upon completion of addition, theresulting mixture was stirred at −2° C. for 10 min, and then a solutionof compound 23A (0.8 g, 2.90 mmol) in THF (15 mL) was added through acannula. The reaction mixture was then allowed to warm to RT where itwas stirred under argon for about 16 hours. At the conclusion of thisperiod, the reaction mixture was quenched with NH₄Cl (saturated aqueoussolution, 20 mL) and then extracted with EtOAc (3×30 mL). The combinedorganic layers were dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under reduced pressure to provide compound 23B and itsregioisomer as yellow oil.

Compound 23C.2-(9-(4-Fluorophenyl)-3-methylenebicyclo[3.3.1]nonan-9-yl)acetic acidand its Regioisomer 23D

Compound 23B and its regioisomer in DMF-H₂O (5 mL, 10:1 v/v) were heatedin 110° C. oil bath for 12 hours. Solvent was removed and the residuewas purified via PrepHPLC to provide 23C as a lightly yellow solid (59mg, 7.1% yield), along with its regioisomer 23D as white solid (186 mg,22.3% yield). ¹H NMR of 23C suggests that it contains about 32% of itsregioisomer (as the structure shown above). 23D (Regioisomer of 23C): ¹HNMR (400 MHz, CD₃OD) δ ppm 7.32-7.38 (m, 2H), 7.00 (t, J=8.6 Hz, 2H),4.55 (t, J=2.6 Hz, 2H), 2.76 (s, 2H), 2.69 (s, 2H), 2.62 (d, J=12.7 Hz,2H), 2.19-2.26 (m, 3H), 2.05-2.19 (m, 2H), 1.71-1.81 (m, 2H), 1.37-1.47(m, 1H). LC/MS (m/z)=287 (M−H)⁺

Compound 23E. 2-(9-(4-Fluorophenyl)-3-oxobicyclo[3.3.1]nonan-9-yl)aceticacid

To a solution of compound 23C (59 mg, 0.205 mmol) in MeOH (3 mL) andCH₂Cl₂ (3 mL) at −78° C. was bubbled O₃/O₂ until a light blue colorpersisted for 10 minutes. Nitrogen gas was bubbled into the abovesolution to get rid of excess O₃. Then 2 mL of Me₂S was added in oneportion. The mixture was gradually warmed to room temperature overnight.Solvent was removed under reduced pressure. The residue was purified viaPrep HPLC to afford compound 23E as white solid (21 mg, 35% yield).LC/MS (m/z)=289 (M−H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.33-7.41 (m, 2H),6.99-7.09 (m, 2H), 3.03 (s, 2H), 2.88-2.99 (m, 2H), 2.67 (s, 2H), 2.51(d, J=18.9 Hz, 2H), 1.73-1.89 (m, 2H), 1.48 (dd, J=13.8, 2.4 Hz, 2H),1.30-1.42 (m, 2H).

Compound 23F.2-((3s,9s)-9-(4-Fluorophenyl)-3-hydroxybicyclo[3.3.1]nonan-9-yl)aceticacid

To a solution of compound 23E (20 mg, 0.069 mmol) in dry THF (0.7 mL) at−78° C. under nitrogen was added L-selectride (0.17 mL, 1 M in THF, 0.17mmol) dropwise. The mixture was stirred at this temperature for 5 hours,then at −20° C. overnight. It was quenched with 20 μL of H₂O₂ (30%aqueous), acidified with HOAc (30 μL). Solvent was evaporated and theresidue was purified via Prep HPLC to afford compound 23F as white solid(16 mg, 80% yield). HPLC Rt (Method B): 6.705 min; HRMS (ESI):Calculated for C₁₇H₂₁FO₃: 292.1474, found: 291.1406 (M−H)⁻. ¹H NMR (400MHz, CDCl₃) δ ppm 7.30-7.35 (m, 2H), 6.93-7.10 (m, 2H), 4.26 (t, J=7.5Hz, 1H), 3.75 (br., 1H, —OH), 3.34-3.40 (m, 1H), 2.86-3.10 (m, 1H),2.57-2.71 (m, 3H), 2.45-2.56 (m, 1H), 2.43 (s, 2H), 1.63-1.80 (m, 3H),1.30-1.53 (m, 2H), 1.07-1.21 (m, 1H).

Example 23

To a suspension of compound 23F (17 mg, 0.058 mmol), 3-hydroxyazetidinehydrochloride salt (9.6 mg, 0.087 mmol), EDAC (16.7 mg, 0.087 mmol),HOBt (11.8 mg, 0.087 mmol) in CH₂Cl₂ (1 mL) was added i-Pr₂NEt (15.2 μL,0.087 mmol). The mixture was stirred at room temperature overnight.Solvent was removed under reduced pressure and the residue was purifiedvia Prep HPLC to afford example 23 as white solid (11 mg, 54% yield).HPLC Rt (Method B): 6.320 min; LC/MS (m/z)=348 (M−H)⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.19-7.34 (m, 2H), 6.97 (t, J=8.6 Hz, 2H), 4.18 (t, J=8.0Hz, 1H), 3.98 (tt, J=6.8, 4.5 Hz, 1H), 3.66-3.83 (m, 1H), 3.39 (dd,J=10.9, 5.3 Hz, 1H), 3.21-3.34 (m, 1H), 2.80-3.12 (m, 6H), 2.30-2.78 (m,4H), 2.07-2.30 (m, 1H), 1.86-2.07 (m, 1H), 1.54-1.73 (m, 2H), 1.22-1.40(m, 2H), 0.97-1.20 (m, 1H).

Example 24

Compound 24A

Compound 24A was synthesized via ozonolysis of compound 23D, followed byL-selectride reduction (see the procedure described in Example 23).Yield 34% (two steps). HPLC Rt (Method B): 5.906 min; LC/MS (m/z)=291(M−H)⁻, ¹H NMR (400 MHz, CDCl₃) δ ppm 7.30-7.39 (m, 2H), 6.93-7.05 (m,2H), 3.24 (quin, J=7.8 Hz, 1H), 2.77 (d, J=9.3 Hz, 2H), 2.63 (s, 2H),2.21-2.34 (m, 2H), 2.01-2.14 (m, 2H), 1.86-2.00 (m, 2H), 1.47-1.60 (m,3H), 1.25-1.38 (m, 2H).

Compound 24B. Methyl2-(9-(4-fluorophenyl)-3-hydroxybicyclo[3.3.1]nonan-9-yl)acetate

To a solution of KOH (aqueous, prepared from 5.0 g of KOH and 7.6 mL ofH₂O) and Et₂O (8 mL) at 0° C. was added1-methyl-3-nitro-1-nitrosoguanidine (MNNG, 460 mg) in portion. The etherlayer turned to yellow. After 5 minutes, the flask was cooled to −78° C.The ether layer was added dropwise to a solution of compound 24A (89.6mg, 0.307 mmol) in CH₂Cl₂ (4 mL) at 0° C., until the yellow colorremained for 10 minutes. Solvent was removed and the residue waspurified in column chromatography (SiO₂, 45% EtOAc in n-hexane) toprovide compound 24B as white solid (93 mg, 99% yield). HPLC Rt (MethodB): 7.011 min; LC/MS (m/z)=307 (M+H)⁺, ¹H NMR (400 MHz, CDCl₃) δ ppm7.29-7.36 (m, 2H), 6.91-7.06 (m, 2H), 3.30 (s, 3H), 3.16-3.28 (m, 1H),2.76 (d, J=9.1 Hz, 2H), 2.61 (s, 2H), 2.21-2.34 (m, 2H), 1.89-2.14 (m,3H), 1.47-1.60 (m, 2H), 1.23-1.40 (m, 3H).

Compound 24C

Compound 24B (46.5 mg, 0.152 mmol), iodobenzene diacetate (IBD, 58.7 mg,0.182 mmol), and iodine (38.6 mg, 0.152 mmol) in cyclohexane (2.5 mL)was heated to 50-65° C. for 4 hours, under the irradiation of a 100 Wnormal light bulb. A solution of sodium sulfite (saturated aqueous, 4mL) was added to remove excess I₂. It was extracted with Et₂O (3×5 mL).Combined organic layers were concentrated to dryness. The residue andBu₃SnH (0.1 mL) in Benzene (3 mL) was heated to reflux for 4 hours.Solvent was removed. The resulting residue was heated in THF (0.5 mL)and LiOH (saturated aqueous, 0.5 mL) at 70° C. overnight. It wasacidified with HOAc (0.4 mL) and the solvent was then removed. Theresidue was purified via Prep HPLC to afford compound 24C as white solid(20 mg, 45% yield). HPLC Rt (Method B): 6.460 min; LC/MS (m/z)=289(M−H)⁻, ¹H NMR (400 MHz, CD₃OD) δ ppm 7.30-7.37 (m, 2H), 6.98-7.06 (m,2H), 4.05 (br. s., 1H), 3.83 (br. s., 1H), 2.79 (br. s., 2H), 2.70 (s,2H), 2.15-2.25 (m, 2H), 2.10 (m, 2H), 1.96 (d, J=12.6 Hz, 2H), 1.70 (m,2H).

Example 24

Example 24 was synthesized from compound 24B and 3-hydroxyazetidinehydrochloride via standard peptide coupling reaction (see procedure inExample 23). Yield: 59%. HPLC Rt (Method B): 5.918 min; LC/MS (m/z)=346(M+H)⁺, ¹H NMR (400 MHz, CDCl₃) δ ppm 7.37 (dd, J=8.7, 5.4 Hz, 2H), 7.07(t, J=7.8 Hz, 2H), 4.18 (tt, J=6.7, 4.3 Hz, 1H), 4.05 (br. s., 1H),3.88-3.98 (m, 1H), 3.82 (br. s., 1H), 3.52 (dd, J=10.9, 3.5 Hz, 1H),3.22-3.30 (m, 1H), 2.95 (dd, J=8.7, 3.7 Hz, 1H), 2.81 (d, J=14.9 Hz,2H), 2.32-2.49 (m, 2H), 2.09-2.25 (m, 4H), 1.95 (d, J=12.4 Hz, 2H),1.53-1.68 (m, 2H).

Example 25

Compounds 25A and 25B

A solution of 2,6-adamantanedione (9.5 g, 57.85 mmol), ethylene glycol(3.22 mL), and TsOH monohydrate (1.099 g, 5.785 mmol) in dry CH₂Cl₂ (870mL) was stirred at room temperature overnight. Solvent was removed underreduced pressure and the residue was purified via column chromatography(SiO₂, 300 g ISCO cartridge, 25% EtOAc in n-Hexane) to provide compound25A as white solid (8.688 g, 72% yield), along with compound 25B aswhite solid (1.868 g, 12.8% yield). 25A: ¹H NMR (400 MHz, CDCl₃) δ ppm3.72 (s, 4H), 2.12 (br. s., 2H), 1.95-2.08 (m, 4H), 1.54-1.68 (m, 6H).

Compound 25C

Compound 25C was synthesized from compound 25A and Meldrum's acidaccording to the procedure described in Example 1. ¹H NMR (400 MHz,CDCl₃) δ ppm 4.00 (s, 4H), 3.97 (br. s., 2H), 2.32 (d, J=12.1 Hz, 4H),1.91 (br. s., 2H), 1.84 (d, J=12.6 Hz, 4H), 1.76 (s, 6H).

Compound 25D

Compound 25D was synthesized from compound 25C and 4-fluorophenylmagnesium bromide according to the procedure described in Example 1.Yield 87%. HPLC Rt (Method B): 5.66 min; LC/MS (m/z)=429 (M−H)⁻, ¹H NMR(400 MHz, CDCl₃) δ ppm 7.20-7.25 (m, 2H), 7.01-7.09 (m, 2H), 4.28 (s,1H), 3.88-4.00 (m, 4H), 2.91 (br. s., 2H), 2.13-2.34 (m, 4H), 1.90 (d,J=12.4 Hz, 3H), 1.67 (br. s., 2H), 1.53-1.60 (m, 1H), 1.49 (s, 3H), 0.79(s, 3H).

Compound 25E

Compound 25E was synthesized from compound 25D via decarboxylation inDMF-H₂O at 110° C. according to the procedure described in Example 1.HPLC Rt (Method B): 4.60 min; LC/MS (m/z)=345 (M−H)⁻; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.30 (dd, J=8.8, 5.3 Hz, 2H), 7.00 (t, J=8.8 Hz, 2H),3.89-3.99 (m, 4H), 2.72 (s, 2H), 2.51 (br. s, 2H), 2.02-2.18 (m, 4H),1.71-1.89 (m, 5H), 1.62 (br. s., 1H).

Compound 25F

A solution of compound 25E (73.7 mg, 0.213 mmol) and TsOH monohydrate(4.81 mg, 0.025 mmol) in 70% acetone-water (1.2 mL) was heated in a 50°C. oil bath for 12 hours. Solvent was removed and the residue waspurified via Prep HPLC to provide compound 25F as white solid (49.4 mg,77% yield). HPLC Rt (Method A): 2.333 min; LC/MS (m/z)=301 (M−H)⁻; ¹HNMR (400 MHz, CDCl₃) δ ppm 7.29-7.37 (m, 2H), 7.04 (t, J=8.7 Hz, 2H),2.84 (s, 2H), 2.75 (br. s., 2H), 2.61 (br. s., 1H), 2.45-2.57 (m, 2H),2.38 (br. s., 1H), 2.19 (d, J=13.1 Hz, 2H), 2.06 (d, J=14.1 Hz, 2H),1.84 (d, J=13.6 Hz, 2H).

Compound 25G

To a solution of compound 25F (20 mg, 0.066 mmol) in THF (0.5 mL) wasadded sodium borohydride (25 mg, 0.66 mmol) slowly. The mixture wasstirred at room temperature for 30 minutes. It was quenched with HOAc(0.1 mL). Solvent was removed and the residue was purified via Prep HPLCto provide compound 25G as white solid (17 mg, 84% yield). HPLC Rt(Method A): 2.260 min; LC/MS (m/z)=303 (M−H)⁻; ¹H NMR (400 MHz, CDCl₃) δppm 7.22-7.33 (m, 2H), 6.99 (t, J=8.8 Hz, 2H), 3.81 (br. s., 1H),2.62-2.70 (dd, 2H), 2.40-2.58 (m, 2H), 2.29 (dd, J=13.6, 3.1 Hz, 1H),2.11-2.23 (m, 1H), 1.82-1.99 (m, 4H), 1.66-1.80 (m, 2H), 1.60 (dd,J=13.0, 2.4 Hz, 1H), 1.52 (dd, J=13.2, 2.2 Hz, 1H).

Compounds 25H and 25I

Racemic 25G (2.0 g) was subjected to chiral SFC purification (ChiralpakAD-H, 250×30 mm ID; 5 μm, Mobile Phase: CO₂/MeOH (70/30), Flow rate: 65ml/min; UV Detection: 220 nm; Injection volume: 2 ml of 76 mg/ml inmethanol) to provide compound 25H (retention time=15.2 minutes) andcompound 25I (retention time=6.1 minutes). HPLC Rt (Method A): 2.260min; LC/MS (m/z)=303 (M−H)⁻; NMR spectra of 25H and 25I are identical tothat of 25G.

25H: [α]^(D)=+30.6° (c=3.6 mg/mL, pyridine, t=25.5° C.). Chiral analyticHPLC: Chiralpak AD, 250×4.6 mm ID; 10 μm, room temperature, mobilephase: CO₂/MeOH/(80/20), Flow rate: 2 mL/min, UV Detection: 220 nm,Retention Time (min): 6.4. e.e>99.9%.

25I: [α]^(D)=−26.5° (c=3.34 mg/mL, pyridine, t=25.5° C.). Chiralanalytic HPLC: Chiralpak AD, 250×4.6 mm ID; 10 μm, room temperature,mobile phase: CO₂/MeOH/(80/20), Flow rate: 2 mL/min, UV Detection: 220nm, Retention Time (min): 3.3. e.e>99.9%.

Alternatively, compounds 25H and 25I can be prepared according to thefollowing enzymatic conversions:

Screening of Ketoreductases

One mL of a solution containing 50 mM potassium phosphate buffer pH 7,0.1 M KCl, 0.5 mM dithiothreitol, 5 mg/mL NADPH tetrasodium salt (6 mM),and compound 25F (1 mg/mL, 3.307 mM) was added to a microfuge tube orwell of a 24-well plate containing about 1 to 5 mg of ketoreductase(available from Biocatalytics Inc.). The solutions were incubated for 15to 17 h at 28° C. and then analyzed by HPLC. Enzymes that gave the mostenantioselective reduction are set forth in Table 25-1 below.

TABLE 25-1 Time Compound 25F Alcohol Compound 25H Ketoreductase hrsmg/mL mg/mL % e.e. KRED 106 15 0.716 0.389 95.49 KRED c1q 15 0.844 0.18695.03 KRED A1Y 16 0.806 0.200 94.84 KRED 125 17 0.869 0.214 94.14 KRED102 15 0.034 1.039 93.27 KRED A1K 17 0.316 0.716 93.22 KRED C1K 15 0.9300.092 91.42 KRED A1O 17 0.780 0.273 90.41 KRED EXP-A1X 16 0.195 0.76080.81 KRED A1L (c1) 17 0.807 0.256 80.45 KRED EXP-B1N 16 0.088 0.87576.34 KRED b1y 15 0.048 0.886 75.73 KRED A1P (c5) 17 1.032 0.026 75.58KRED A1H (b3) 17 1.017 0.027 68.62 KRED EXP-A1U 16 0.104 0.830 65.18KRED b1t 15 0.991 0.028 62.76 KREDEXP-B1G 16 0.373 0.649 61.19Screening of Yeast Strains for Reduction of Compound 25F

Two mL F7 medium (1% malt extract, 1% yeast extract, 0.1% peptone and 2%dextrose adjusted to pH 7) was added to each well of 24-well platescontaining 69 frozen yeast cultures (0.1 mL broth with 20% glycerol) forscreening for reduction of compound 25F. The plates were incubated for21 h at 28° C. and 600 rpm, then 10 μL of 100 mg/mL compound 25Fslurried in methanol was added to each well. Incubation was continuedfor 48 h before analysis by HPLC as described above. Strains that gavethe most enantioselective reduction are set forth in Table 25-2 below.

TABLE 25-2 Compound 25F Alcohol Compound 25H Strain SC # ATCC # mg/mLmg/mL % e.e. Pichia membranafaciens 13859 20101 0.399 0.010 100.00Pichia anomala 16139 8168 0.323 0.009 100.00 Pichia anomala 16140 200290.350 0.010 100.00 Pichia anomala 16141 36995 0.395 0.020 100.00 Pichiaanomala 16143 66346 0.489 0.022 100.00 Pichia anomala 16145 20144 0.4480.013 100.00 Pichia ciferrii 16170 14091 0.234 0.031 100.00 Hansenulafabianii 13894 58045 0.074 0.516 100.00 Candida utilis 16524 42181 0.2130.108 100.00 Candida boidini 13821 0.300 0.082 100.00 Pichia silvicola16160 16768 0.180 0.110 69.79 Rhodotorula glutinis 16293 201718 0.2060.225 69.35 Hansenula polymorpha 13896 62809 0.268 0.315 51.54

Enzymatic Conversion of Compound 25F to Compound 25H

A 350 mL reaction mixture containing 0.1 M potassium phosphate buffer pH8, 0.1 M KCl, 1 mM dithiothreitol, 1 mM NADP, glucose dehydrogenase (35mg, 1540 U from Amano), glucose (3.5 g, 1.389 mmoles), ketoreductaseKRED-102 (70 mg, 511 U from Biocatalytics) and compound 25F (700 mg,0.165 mmoles) was incubated at 28° C. HPLC analysis after 17 h showedthere was no remaining compound 25F.

The reaction mixture (350 mL, pH 7.56) was then acidified to pH 3.0 with5M H₂SO₄ (4.75 g) and extracted with ethylacetate (2×250 mL). Thecombined ethylacetate phases were washed with 100 mL of 15% NaCl, driedover MgSO₄ for 2 h, and filtered. Solvent removal of the filtrate gave awhite solid, which was further dried in a vacuum oven at roomtemperature overnight to give 745 mg of crude compound 25H (Yield 108%,AP 94, e.e. 96.1%).

Enzymatic Conversion of Ketone Compound 25F to Compound 25I Screening ofKetoreductases

One mL of a solution containing 50 mM potassium phosphate buffer pH 7,0.1 M KCl, 0.5 mM dithiothreitol, 5 mg/mL NADPH tetrasodium salt (6 mM),and compound 25F (1 mg/mL, 3.307 mM) was added to a microfuge tube orwell of a 24-well plate containing about 1 to 5 mg keto reductase(available from Biocatalytics Inc.). The solutions were incubated for 15to 17 h at 28° C. then analyzed by HPLC. Enzymes giving the mostenantioselective reduction are shown in the Table 25-3 set forth below.

TABLE 25-3 Time Compound 25F Alcohol Compound 25I Ketoreductase hrsmg/mL mg/mL % e.e. KRED 101 15 0.570 0.537 93.08 KRED 103 15 0.668 0.44792.82 KRED 112 15 0.725 0.391 92.39 KRED A1V 16 0.028 0.897 92.09 KRED114 15 0.669 0.448 85.03Screening of Yeast Strains for Reduction of Compound 25F to Compound 25I

Yeast strains were screened for reduction of Compound 25F in a similarmanner as described above. Strains giving the most enantioselectivereduction are set forth in the Table 25-4 below.

TABLE 25-4 Compound 25F Alcohol Compound 25I Strain SC # ATCC # mg/mLmg/mL % e.e. Pichia methanolica 13825 58403 0.070 0.245 100.00 Pichiamethanolica 16413 58372 0.260 0.245 100.00 Pichia methanolica 1641456508 0.237 0.408 100.00 Pichia methanolica 16415 56509 0.120 0.472100.00 Pichia methanolica 16416 46071 0.097 0.320 100.00 Rhodotorulaglutinis 16267 26207 0.277 0.086 100.00 Pichia methanolica 13860 0.1070.302 100.00 Pichia methanolica 16413 0.166 0.175 100.00 Pichiamethanolica 16116 56508 0.035 0.286 94.98 Pichia methanolica 13860 565100.023 0.303 94.95

Example 25

Example 25 was synthesized from compound 25H and 3-hydroxyazetidinehydrochloride according to the procedure in Example 21. HPLC Rt (MethodC): 5.376 min; LC/MS (m/z)=360 (M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ ppm7.38 (br. s, 2H), 7.09 (t, J=8.3 Hz, 2H), 3.99-4.13 (m, 1H), 3.77-3.87(m, 1H), 3.74 (br. s, 1H), 3.40 (ddd, J=10.4, 5.1, 4.9 Hz, 1H),3.20-3.36 (m, 1H), 2.98-3.14 (m, 1H), 2.33-2.68 (m, 5H), 2.21 (d, J=13.6Hz, 1H), 1.82-2.12 (m, 4H), 1.75 (d, J=13.6 Hz, 1H), 1.66 (br. s., 1H),1.46-1.60 (m, 2H). Chiral analytic HPLC: Chiralpak AD, 250×4.6 mm ID; 10μm, room temperature, mobile phase: CO₂/MeOH/(80/20), Flow rate: 2mL/min, UV Detection: 220 nm, Retention Time (min): 10.64. e.e>99.9%.

Example 26

Compound 26A

Compound 26A was synthesized from compound 25C by following theprocedures described in Example 25. HPLC Rt (Method B): 6.263 min; LC/MS(m/z)=285 (M−H)⁻; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.27-7.39 (m, 4H),7.15-7.24 (m, 1H), 3.81 (br. s., 1H), 2.64-2.80 (m, 2H), 2.47-2.62 (m,2H), 2.30 (dq, J=13.7, 3.3 Hz, 1H), 2.14-2.24 (m, 1H), 1.87-2.02 (m,4H), 1.68-1.79 (m, 2H), 1.65 (dd, J=13.0, 2.7 Hz, 1H), 1.47-1.57 (m,1H). ¹³C NMR (101 MHz, CDCl₃) δ ppm 176.06, 144.22, 128.27, 126.41,126.00, 74.25, 45.95, 44.86, 34.03, 33.38, 32.34, 32.26, 31.56, 31.44,26.86, 26.26. Chiral analytic HPLC: Chiralpak AD, 250×4.6 mm ID; 10 μm,room temperature, mobile phase: CO₂/MeOH/(70/30), Flow rate: 3 ml/min,UV Detection: 220 nm, Retention Time (min): 6.9. e.e>99.9%.

Example 26

Example 26 was synthesized from compound 26A by following the proceduresdescribed in Example 25. HPLC Rt (Method C): 7.89 min; LC/MS (m/z)=342(M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.27 (br. s., 4H), 7.11-7.21 (m,1H), 3.78-3.93 (m, 1H), 3.60-3.75 (m, 2H), 3.24-3.34 (m, 1H), 3.02 (t,J=7.3 Hz, 0.5H), 2.92 (d, J=5.7 Hz, 1H), 2.83 (dd, J=9.0, 4.2 Hz, 0.5H),2.49-2.63 (m, 2H), 2.17-2.49 (m, 3H), 2.06-2.17 (m, 1H), 1.75-2.06 (m,4H), 1.66 (d, J=13.6 Hz, 1H), 1.38-1.59 (m, 3H).

Example 27

Compound 27A

Potassium tert-butoxide (39.5 mg, 0.352 mmol) was added in a smallportion to a well stirred, moisture-protected suspension of compound 25F(21.3 mg, 0.070 mmol), TOSMIC (19.26 mg, 0.099 mmol), and ethanol (6.89μL) in 1,2-dimethoxyethane (403 μL) at 0° C. (ice water bath). Aftercompletion, the mixture was warmed to room temperature, then placed in a37° C. oil bath and stirred for 1 hour. LCMS showed the reaction wascompleted. The reaction was quenched with HOAc (0.1 mL). Solvent wasremoved under reduced pressure. The residue was dissolved in MeOH, andpurified via Prep HPLC (Phenomenex AXIA 5 u C18 30×100 mm, Flow rate: 40mL, Solvent A: 90% H₂O and 10% MeOH with 0.1% TFA, Solvent B: 90% MeOHand 10% H₂O with 0.1% TFA. 0% to 100% B in 12 min gradient, stop at 15min, the product RT=11.146 min) to provide compound 27A as white solid(14.6 mg, 66% yield). HPLC Rt (Method B): 7.125 min; LC/MS (m/z)=312(M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.37 (dd, J=8.7, 5.4 Hz, 2H), 7.03(t, J=8.8 Hz, 2H), 3.03 (br. s., 1H), 2.63-2.79 (m, 4H), 2.42 (dd,J=13.9, 2.8 Hz, 1H), 2.32 (d, J=13.6 Hz, 1H), 2.09-2.26 (m, 2H),1.90-2.01 (m, 3H), 1.80-1.90 (m, 2H), 1.60-1.69 (m, 1H).

Example 27

Example 27 was synthesized from compound 27A and 3-hydroxyazetidinehydrochloride via standard peptide coupling reaction (see procedure inExample 23). Yield: 62.3%. HPLC Rt (Method C): 6.741 min; LC/MS(m/z)=369 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.38 (br. s., 2H), 7.11(t, J=8.8 Hz, 2H), 4.00-4.12 (m, 1H), 3.76-3.87 (m, 1H), 3.40 (dd,J=10.4, 4.5 Hz, 1H), 3.32-3.37 (m, 1H), 2.96-3.12 (m, 2H), 2.72 (br. s.,2H), 2.58 (dd, J=18.8, 13.3 Hz, 1H), 2.30-2.52 (m, 3H), 2.09-2.23 (m,2H), 1.77-1.99 (m, 5H), 1.66 (d, J=2.8 Hz, 1H).

Example 28

Compound 28A. tert-Butyl 3-(2H-tetrazol-5-yl)azetidine-1-carboxylate

Tert-butyl 3-cyanoazetidine-1-carboxylate (493.8 mg, 2.713 mmol) andazidotrimethyltin (920 mg, 4.34 mmol) in dry toluene (13 mL) were placedin sealed tube and heated in 100° C. oil bath for 18 hours. Solvent wasremoved under reduced pressure and the residue was purified via PrepHPLC to provide compound 28A as a light yellow oil (474 mg, 77.6%yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.42-4.52 (m, 2H), 4.28-4.35 (m,2H), 4.18-4.28 (m, 1H), 1.43-1.49 (s, 9H).

Compound 28B and Regioisomer 28C

Compound 28A (0.474 mg, 2.107 mmol) and K₂CO₃ (291 mg, 2.107 mmol) inacetone (4 mL) was heated to reflux for 2 hours under argon. Methyliodide (138 μL, 2.21 mmol) was introduced. The resulting mixture washeated to reflux for another 6 hours. EtOAc (10 mL) was added to thecooled mixture, which was stirred for 5 minutes. Solid was filtered offand rinsed with EtOAc (3×5 mL). Organic solvent was evaporated. Theresidue was purified via column chromatography (SiO₂, 40-60%EtOAc/n-Hexane) to provide compound 28B as colorless oil (228 mg, 45.3%yield), along with compound 28C as colorless oil (131 mg, 26% yield).28B: ¹H NMR (400 MHz, CDCl₃) δ ppm 4.30-4.40 (m, 2H), 4.35 (s, 3H),4.17-4.25 (m, 2H), 3.99-4.11 (m, 1H), 1.46 (s, 9H). 28C: ¹H NMR (400MHz, CDCl₃) δ ppm 4.39 (t, J=8.6 Hz, 2H), 4.30 (br. s., 2H), 3.95-4.06(m, 1H), 4.01 (s, 3H), 1.41-1.50 (m, 9H).

Compound 28D

To a solution of compound 28B (228 mg, 0.954 mmol) in MeOH (8.5 mL) wasadded 4 M HCl in dioxane (3.3 mL). The mixture was stirred at roomtemperature for 5 hours. Solvent was removed under reduced pressure toafford compound 28D as lightly yellow solid (198 mg, 100% yield).

Example 28

Example 28 was synthesized from compound 28D and the correspondingcarboxylic acid 26A by following the procedures described in Example 26.HPLC Rt (Method B): 6.450 min; LC/MS (m/z)=408 (M+H)⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.28-7.45 (m, 4H), 7.09-7.22 (m, 1H), 4.31 (d, rotomers,3H), 4.16-4.28 (m, 2H), 4.06-4.16 (m, 1H), 3.96-4.06 (m, 1H), 3.83 (br.s., 1H), 3.44-3.59 (m, rotomer, 1.5H), 3.21-3.36 (m, 1H), 3.05-3.15 (m,rotomer, 0.5H), 2.69-2.80 (m, 1H), 2.32-2.69 (m, 3H), 1.46-2.26 (m, 9H).

Example 29

Compound 29A

Compound 29A was synthesized from compound 25C by following theprocedures described in Example 25. HPLC Rt (Method C): 7.27 min; LC/MS(m/z)=319 (M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.31-7.40 (m, 2H),7.24-7.31 (m, 2H), 3.75 (br. s., 1H), 2.63-2.79 (m, 2H), 2.47-2.61 (m,2H), 2.31-2.42 (m, 1H), 2.22 (dd, J=13.5, 2.1 Hz, 1H), 1.95-2.06 (m,2H), 1.85-1.95 (m, 2H), 1.75 (dd, J=13.6, 2.3 Hz, 1H), 1.67 (br. s.,1H), 1.56 (d, 2H).

Compound 29B

Compound 29A (56 mg, 0.175 mmol), nickel(II)bromide (275 mg, 1.257mmol), sodium cyanide (25.7 mg, 0.524 mmol), and zinc cyanide (36.5 mg,0.311 mmol) were placed in microwave vial under argon atmosphere. NMP(14 mL) was added. The reaction mixture was heated to 200° C. inmicrowave for 40 min. The resulting solid was filtered off and rinsedwith MeOH. The filtrate was concentrated under reduced pressure toafford the crude product. The crude product was purified via Prep HPLCto provide compound 29B as a light brown oil (35 mg, 60.7% yield). LC/MS(m/z)=310 (M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.68 (t, J=8.6 Hz, 2H),7.59 (t, J=8.1 Hz, 2H), 3.98 (s, 2H), 2.71-2.86 (m, 2H), 2.54-2.70 (m,2H), 2.32-2.53 (m, 1H), 2.06-2.29 (m, 2H), 2.02 (dd, J=13.4, 2.5 Hz,1H), 1.43-1.98 (m, 6H).

Example 29

Example 29 was synthesized from compound 29B and 3-hydroxyazetidinehydrochloride via standard peptide coupling reaction (see procedure inExample 23). Yield: 64.8%. HPLC Rt (Method C): 4.925 min; LC/MS(m/z)=367 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.67 (d, J=7.5 Hz, 2H),7.52 (d, J=8.3 Hz, 2H), 4.15-4.27 (m, 1H), 3.84-3.97 (m, 1H), 3.82 (br.s., 1H), 3.75 (t, J=6.4 Hz, 1H), 3.50 (td, J=10.9, 4.2 Hz, 1H),3.21-3.44 (m, 1H), 2.86-3.12 (m, 1H), 2.67 (d, J=15.4 Hz, 1H), 2.46-2.60(m, 2H), 2.29-2.46 (m, 2H), 2.15-2.29 (m, 1H), 1.93-2.12 (m, 1H),1.39-1.92 (m, 6H).

Example 30

Compound 30A

To a solution of compound 25C (0.278 g, 0.831 mmol) in dry THF (5 mL) at−78° C. under argon was added methyl magnesium bromide (0.97 mL, 2.91mmol, 3.0 M solution in THF) slowly. The mixture was stirred andgradually warmed to room temperature overnight. NH₄Cl (saturatedaqueous, 10 mL) was added to quench the reaction. It was extracted withEtOAc (3×15 mL). Combined organic layers were dried (Na₂SO₄),concentrated to afford white solid. A suspension of this solid inDMF-H₂O (5 mL, 10:1 v/v) was heated in 110° C. oil bath for 12 hours.Solvent was removed under reduced pressure. The residue was purified viaPrep HPLC to provide compound 30A as white solid (120 mg, 54.3% twosteps).

Compound 30B

Compound 30B was synthesized from compound 30A via the proceduredescribed in Example 25. Yield: 69% for two steps. LC/MS (m/z)=223(M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ ppm 3.67-3.75 (m, 1H), 2.41-2.58 (m,2H), 2.22 (ddd, J=13.6, 6.8, 3.4 Hz, 2H), 2.00 (dd, J=13.0, 1.6 Hz, 2H),1.86 (br. s., 1H), 1.75-1.85 (m, 3H), 1.59 (br. s., 1H), 1.54 (br. s.,1H), 1.51 (br. s., 2H), 1.20 (s, 3H). ¹³C NMR (101 MHz, CD₃OD) δ ppm176.87, 75.69, 44.54, 39.36, 37.05, 36.10, 35.40, 35.16, 32.94, 32.90,27.52, 23.89.

Compound 30C

To a suspension of NaH (114 mg, 95%, 4.51 mmol) in dry DMF (10 mL) at 0°C. was added tert-butyl 3-hydroxyazetidine-1-carboxylate (724.7 mg, 4.1mmol) under argon. The mixture was heated in 40° C. oil bath for 1 hour.To the above mixture at room temperature was added6-chloronicotinonitrile (638 mg, 4.51 mmol). After heating at 40° C. inan oil bath for 3 hours, the mixture was allowed to cool to roomtemperature overnight. It was quenched with water (50 mL) and thenextracted with EtOAc (3×20 mL). The combined organic layers were dried(Na₂SO₄) and concentrated. The crude product was purified via columnchromatography (SiO₂, 25-30% EtOAc/n-Hexane) to provide compound 30C asa white solid (1.0 g, 88.6%). LC/MS (m/z)=276 (M+H)⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 8.45 (d, J=2.2 Hz, 1H), 7.84 (dd, J=8.8, 2.2 Hz, 1H), 6.89(d, J=9.2 Hz, 1H), 5.30-5.42 (m, 1H), 4.34 (dd, J=11.0, 6.6 Hz, 2H),3.98 (dd, J=11.2, 4.2 Hz, 2H), 1.46 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δppm 164.26, 156.11, 151.86, 141.43, 116.88, 112.00, 103.38, 79.84,65.78, 56.32, 28.35.

Compound 30D

Compound 30D was synthesized from compound 30C via the proceduredescribed in Example 28. LC/MS (m/z)=176 (M+H)⁺.

Example 30

Example 30 was synthesized from compound 30B and 30D via standardpeptide coupling reaction (see procedure in Example 23). LC/MS (m/z)=382(M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.46 (d, J=2.2 Hz, 1H), 7.85 (dd,J=8.6, 2.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 5.33-5.45 (m, 1H), 4.56 (dd,J=8.3, 6.6 Hz, 1H), 4.40 (dd, J=11.2, 6.8 Hz, 1H), 4.14 (dd, J=9.7, 4.0Hz, 1H), 4.05 (dd, J=11.2, 4.2 Hz, 1H), 3.77 (br. s., 1H), 3.50 (s, 1H),2.32-2.43 (m, 1H), 2.11-2.29 (m, 3H), 1.89-2.03 (m, 2H), 1.85 (br. s.,3H), 1.72 (br. s., 1H), 1.44-1.64 (m, 3H), 1.17 (s, 3H).

Example 31

Compound 31A

Compound 31A was synthesized from 4-oxo-1-adamantanecarboxylic acid andMeldrum's acid via the procedure described in Example 25. ¹H NMR (400MHz, CD₃OD) δ ppm 4.06 (br. s., 2H), 2.00-2.26 (m, 9H), 1.86-1.99 (m,2H), 1.75 (s, 3H), 1.74 (s, 3H); ¹³C NMR (101 MHz, CD₃OD) δ ppm 187.06,162.36, 113.90, 105.28, 41.94, 40.86, 40.40, 38.89, 36.78, 28.72, 27.11,26.93.

Compound 31B and its Regioisomer 31C

Compound 31B and its regioisomer 31C were synthesized from compound 31Aand 4-fluorophenyl magnesium bromide via cuprate addition reaction anddecarboxylation reaction using the procedures described in Example 25.The ratio of 31B:31C is about 2.3:1.

31B: LC/MS (m/z)=331 (M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.33-7.44 (m,2H), 7.02 (t, J=8.8 Hz, 2H), 2.77 (br. s., 2H), 2.72 (s, 2H), 2.30 (d,J=12.9 Hz, 2H), 2.08 (br. s., 1H), 1.98 (d, J=12.9 Hz, 2H), 1.87 (br.s., 2H), 1.66-1.82 (m, 4H)

31C: LC/MS (m/z)=331 (M−H)⁻; ¹H NMR (400 MHz, CD₃OD) δ ppm 7.35-7.42 (m,2H), 6.98-7.06 (m, 2H), 2.73-2.81 (m, 2H), 2.68 (s, 2H), 2.43 (d, J=13.1Hz, 2H), 1.94 (d, J=13.1 Hz, 2H), 1.79-1.90 (m, 6H), 1.57 (d, 2H).

Compound 31D

To a solution of Compound 31B (27.6 mg, 0.083 mmol),2-(trimethylsilyl)ethanol (10.3 mg, 0.087 mmol), and DMAP (15.2 mg,0.125 mmol) in dry CH₂Cl₂ at 0° C. was added EDAC (19.1 mg, 0.10 mmol),followed by i-Pr₂NEt (17.4 μL, 0.10 mmol). The mixture was stirred andgradually warmed to room temperature overnight. Solvent was removedunder reduced pressure; the residue was purified via Prep HPLC toprovide compound 31D as white solid (25.3 mg, 70.4% yield). HPLC Rt(Method A): 6.335 min; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.19-7.27 (m, 2H),6.97 (t, J=8.5 Hz, 2H), 3.71-3.81 (m, 2H), 2.70 (br. s., 2H), 2.65 (s,2H), 2.21 (d, J=12.6 Hz, 2H), 2.10 (br. s., 1H), 1.95 (d, J=12.6 Hz,2H), 1.84 (br. s., 2H), 1.74 (t, J=14.6 Hz, 4H), 0.57-0.67 (m, 2H),−0.06 (s, 9H).

Compound 31E

A mixture of compound 31D (24 mg, 0.0556 mmol), HOBt (11.3 mg, 0.0834mmol), NH₄Cl (6 mg, 0.111 mmol), EDAC (16 mg, 0.0834 mmol), and i-Pr₂NEt(34 μL, 0.195 mmol) in dry DMF (0.7 mL) was heated in 65° C. oil bathfor 2 hours. Solvent was removed and the residue was purified via PrepHPLC to provide compound 31E as white solid (22.8 mg, 95% yield). HPLCRt (Method A): 7.266 min; LC/MS (m/z)=432 (M+H)⁺; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.26-7.36 (m, 2H), 7.00-7.11 (m, 2H), 6.82 (br. s., 1H),5.76 (br. s., 1H), 3.78-3.88 (m, 2H), 2.82 (br. s, 2H), 2.72 (s, 2H),2.30 (d, J=13.1 Hz, 2H), 2.21 (d, J=2.8 Hz, 1H), 2.00 (d, J=12.4 Hz,2H), 1.90 (br. s., 2H), 1.72-1.88 (m, 4H), 0.62-0.74 (m, 2H), −0.03-0.04(m, 9H). ¹³C NMR (101 MHz, CDCl₃) δ ppm 182.45, 171.51, 162.27, 161.20,159.83, 139.65, 139.62, 127.90, 127.81, 115.32, 115.11, 62.20, 45.38,44.78, 40.36, 40.10, 34.80, 32.67, 31.65, 26.71, 17.06, −1.67.

Compound 31F

To a solution of compound 31E (22.8 mg, 0.0529 mmol) in pyridine (0.5mL) at room temperature was added MsCl (16.4 mL, 0.211 mmol). Themixture was stirred at room temperature overnight. Solvent was removedand the residue was purified via Prep HPLC to provide compound 31F aswhite solid (16.7 mg, 76.4% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm7.25-7.34 (m, 2H), 7.08 (t, J=8.6 Hz, 2H), 3.79-3.88 (m, 2H), 2.79 (br.s., 2H), 2.70 (s, 2H), 2.14-2.34 (m, 4H), 2.07 (br. s., 2H), 1.80-1.99(m, 4H), 1.75 (br. s., 1H), 0.63-0.73 (m, 2H), −0.04-0.04 (m, 9H).

Compound 31G

A solution of compound 31F (16.7 mg, 0.040 mmol) in TBAF-HOAc (0.25 mL,prepared from 1.0 M TBAF in THF and HOAc in equal molar ratio) wasplaced in sealed tube and heated in 70° C. oil bath for 48 hours.Solvent was removed and the residue was purified via Prep HPLC toprovide compound 31G as white solid (10 mg, 79% yield). LC/MS (m/z)=312(M−H)⁻; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.24 (dd, J=8.8, 5.3 Hz, 2H), 7.03(t, J=8.6 Hz, 2H), 2.73 (br. s., 2H), 2.69 (s, 2H), 2.08-2.24 (m, 5H),2.03 (br. s., 2H), 1.88 (d, J=12.7 Hz, 2H), 1.81 (d, 2H).

Example 31

Example 31 was synthesized from compound 31G and 3-hydroxyazetidinehydrochloride via standard peptide coupling reaction (see procedure inExample 23). HRMS (ESI): Calculated for C₂₂H₂₅FN₂O₂: 368.1900, found:369.1977 (M+1). LC/MS (m/z)=369 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm7.31 (dd, J=8.8, 5.3 Hz, 2H), 7.10 (d, J=6.2 Hz, 2H), 4.19 (d, J=4.0 Hz,1H), 3.92 (dd, J=9.7, 7.0 Hz, 1H), 3.51 (dd, J=10.3, 3.7 Hz, 1H),3.22-3.30 (m, 1H), 2.95 (dd, J=8.8, 3.5 Hz, 1H), 2.79 (d, J=18.9 Hz,2H), 2.33-2.47 (m, 2H), 2.32 (dd, J=6.6, 3.5 Hz, 2H), 2.12 (d, J=9.7 Hz,3H), 2.02 (br. s., 2H), 1.76-1.92 (m, 4H).

Example 32

Compound 32A

Compound 32A was synthesized from compound 31C via the proceduresdescribed in Example 31. LC/MS (m/z)=330 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD)δ ppm 7.31-7.34 (m, 2H), 6.96-7.07 (m, 2H), 3.39 (dt, J=3.3, 1.6 Hz,2H), 2.76 (br. s., 2H), 2.68 (s, 2H), 2.39 (d, J=14.4 Hz, 2H), 1.80-1.96(m, 6H), 1.55 (d, 2H).

Compound 32B

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.7 g,4.041 mmol) and phosgene (2.2 mL, 1 M in PhMe, 4.243 mmol) in dry CH₂Cl₂(10 mL) at −15° C. was added Et₃N (0.62 mL, 4.445 mmol) slowly. Themixture was carefully warmed to room temperature overnight. Solvent wasremoved under reduced pressure. Et₂O (15 mL) was added. The precipitatewas filtered off and rinsed with Et₂O (3×5 mL). The combined organiclayers were evaporated to dryness to afford the crude chloroformate. Toa mixture of methyl amine (1.04 mL, 12.123 mmol, 40% w/w aqueous) in THF(5 mL) and Na₂CO₃ (4 mL, saturated aqueous) was added slowly the abovecrude chloroformate. The mixture was stirred at room temperature for 40minutes. The organic layer was separated and the aqueous layer wasextracted with Et₂O (3×5 mL). The combined organic layers were dried andevaporated. The residue was purified via column chromatography (SiO₂,35-40% EtOAc in n-hexane) to provide compound 32B as white solid (0.656g, 70.5% yield). ¹H NMR (400 MHz, CDCl₃) δ ppm 5.20 (br. s., 1H), 5.11(dd, J=6.2, 3.7 Hz, 1H), 4.15-4.29 (m, 2H), 3.81-3.97 (m, 2H), 2.79 (d,J=4.8 Hz, 3H), 1.39-1.51 (m, rotomer, 9H); ¹³C NMR (101 MHz, CDCl₃) δppm 156.18, 156.01, 79.75, 63.34, 28.31, 27.39, 22.92.

Compound 32C

Compound 32C was synthesized from compound 32B via Boc-deprotection in 4M HCl in dioxane followed the procedure described in Example 28.

Example 32

Example 32 was synthesized from compound 32A and 32C via standardpeptide coupling reaction (see procedure in Example 23). LC/MS (m/z)=444(M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.26 (dd, J=8.6, 5.6 Hz, 2H), 7.00(br. s., 2H), 6.53 (br. s., 1H), 5.86 (br. s., 1H), 4.53-4.71 (m, 2H),3.90 (dd, J=10.7, 7.5 Hz, 1H), 3.51 (d, J=7.6 Hz, 1H), 3.39-3.47 (m,1H), 2.77-2.85 (m, 1H), 2.72-2.77 (m, 1H), 2.70 (d, J=4.8 Hz, 3H),2.58-2.66 (m, 1H), 2.46 (d, J=13.1 Hz, 1H), 2.37-2.44 (m, 1H), 2.26-2.37(m, 1H), 2.15 (d, 1H), 1.66-1.94 (m, 7H), 1.47 (dd, 2H).

Example 33

Compound 33A

A mixture of Example 12 (30 mg, 0.10 mmol), acetonitrile (0.073 mL) andconcentrated sulfuric acid (0.154 mL) was heated at 45° C. overnight.The mixture was poured onto ice (5 g) and warmed to room temperature. Itwas extracted with Et₂O (2×10 mL). The combined organic phases weredried (MgSO₄) and concentrated. The residue was purified via Prep-HPLCto provide compound 33A as a white solid (11.0 mg, 33% yield). HPLC Rt(Method A): 3.70 min; LC/MS (m/z)=344 (M−H)⁻. ¹H NMR (400 MHz, CD₃OD) δppm 7.53 (s, 1H), 7.37 (dd, J=8.79, 5.27 Hz, 2H), 7.00 (t, J=8.79 Hz,2H), 2.76-2.84 (m, 3H), 2.73 (s, 3H), 1.83-1.95 (m, 8H), 1.79 (d,J=13.62 Hz, 2H), 1.54 (d, J=11.86 Hz, 2H).

Example 33

Example 33 was synthesized from compound 33A and 3-hydroxyazetidinehydrochloride via standard peptide coupling reaction (see the proceduredescribed in Example 23). HRMS (ESI): Calculated for C₂₃H₂₉FN₂O₃:400.2162, found: 401.2223 (M+1). HPLC Rt (Method B): 6.82 min; ¹H NMR(400 MHz, CD₃OD) δ ppm 7.38 (br. s., 2H), 7.09 (t, J=8.6 Hz, 2H),4.01-4.12 (m, 1H), 3.81 (dd, J=9.9, 7.7 Hz, 1H), 3.39 (dd, J=10.5, 4.4Hz, 1H), 3.31-3.37 (m, 2H), 3.09 (dd, J=8.6, 4.6 Hz, 1H), 2.70-2.90 (m,4H), 2.61 (d, J=13.2 Hz, 1H), 2.45 (d, J=13.2 Hz, 1H), 1.83-1.98 (m,7H), 1.76 (t, J=12.5 Hz, 2H), 1.53 (d, 2H).

Example 34

Compound 34A. N′-acetyl-1-benzhydrylazetidine-3-carbohydrazide

To a solution of 1-benzhydrylazetidine-3-carboxylic acid (2.097 g, 7.845mmol) and acetohydrazine (0.967 g, 11.767 mmol) in DMF (40 mL) was addedHOBt (1.59 g, 11.767 mmol) and EDAC (2.255 g, 11.767 mmol), followed byi-Pr₂NEt (2.1 mL, 11.767 mmol). The mixture was stirred at roomtemperature overnight. Solvent was removed and the residue was purifiedvia Prep HPLC to provide compound 34A as white solid (2.4 g, 95% yield).LC/MS (m/z)=324 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.48 (d, J=7.1 Hz,4H), 7.28-7.42 (m, 6H), 5.40 (s, 1H), 4.30 (br. s., 2H), 3.84-4.10 (m,3H), 1.84-2.07 (m, rotomer, 3H).

Compound 34B

To a solution of compound 34A (760 mg, 2.350 mmol) in acetonitrile (15ml) was added i-Pr₂NEt (2.372 ml, 13.58 mmol) and triphenylphosphine(1.091 g, 4.16 mmol). After stirring at RT for 5 mins, hexachloroethane(0.351 mL, 3.10 mmol) was added. The mixture was stirred at RTovernight. Solvent was evaporated off. The residue was partitionedbetween EtOAc (50 mL) and H₂O (25 mL). Organic layer was separated; theaqueous layer was extracted with EtOAc (50 mL). The combined organiclayers were dried (MgSO₄), concentrated. The residue was purified firstvia column chromatography (0-15% EtOAc in n-hexane), then via Prep HPLCto provide compound 34B as a colorless oil (10 mg, 1.5% yield). LC/MS(m/z)=306 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ ppm 6.98-7.63 (m, 10H), 5.76(s, 1H), 4.24-4.56 (m, 5H), 2.49-2.62 (m, 3H).

Compound 34C

To a solution of compound 34B (10 mg, 0.033 mmol) in MeOH (2.0 mL) wasadded Pd/C (3.0 mg, 10% activated). The reaction mixture was stirred atroom temperature for 2.5 hours under an H₂ atmosphere (balloon). Thecatalyst was filtered off and solvent was evaporated to provide compound34C as a colorless oil (12 mg). LC/MS (m/z)=140 (M+H)⁺.

Example 34

Example 34 was synthesized from compound 26A and 34C via standardpeptide coupling reaction (see the procedure described in Example 23).LC/MS (m/z)=408 (M+H)⁺. HPLC Rt (Method B): 6.08 min; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.21-7.35 (m, 4H), 7.04-7.16 (m, 1H), 3.93-4.03 (m, 1H),3.83-3.91 (m, 1H), 3.74 (br. s., 1H), 3.31-3.45 (m, 1H), 3.23-3.30 (m,0.5H), 3.15 (t, J=8.6 Hz, 0.5H), 3.05-3.12 (m, 0.5H), 2.99 (t, J=8.8 Hz,0.5H), 2.47-2.64 (m, 2H), 2.45 (two singlets, rotomers, 3H), 2.29-2.43(m, 2H), 1.36-2.22 (m, 11H).

Example 35

Compound 35A

To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (200mg, 1.0 mmol) in THF (10 mL) at 0° C. was added Et₃N (102 mg, 2.0 mmol),followed by ethyl chloroformate (130 mg, 1.3 mmol). After stirring at 0°C. for 30 minutes, a solution of 2-hydrazinylpyridine in THF (2.0 ml)was added. The mixture was warmed up and stirred at room temperatureovernight. The precipitate was filtered off, the solvent was evaporated,and the resulting residue was purified via column chromatography (SiO₂,0-100% EtOAc in n-hexanes) to provide compound 35A as a yellow oil (189mg, 64% yield). LC/MS (m/z)=294 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm7.87-8.23 (m, 1H), 7.30-7.70 (m, 1H), 6.70-6.93 (m, 1H), 6.65 (d, J=8.25Hz, 1H), 4.05-4.16 (m, 2H), 4.02 (t, J=8.52 Hz, 2H), 3.94 (t, J=8.79 Hz,1H), 1.32-1.45 (m, 9H).

Compound 35B

To a solution of compound 35A in CH₂Cl₂/CCl₄ (12.0 mL/6.0 mL) at 0° C.was added i-Pr₂NEt (838 mg, 6.5 mmol), followed by PEt₃ (381 mg, 3.23mmol). The mixture was warmed to room temperature and stirred overnight.The solvent was evaporated and the residue was purified via columnchromatography (SiO₂, 0-100% EtOAc in n-hexanes) to provide compound 35Bas a yellow oil (158 mg). LC/MS (m/z)=275 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.88 (d, J=7.03 Hz, 1H), 7.77 (d, J=9.23 Hz, 1H), 7.25-7.30(m, 1H), 6.87 (t, J=6.81 Hz, 1H), 4.44 (t, J=8.57 Hz, 4H), 4.12-4.27 (m,1H), 1.44 (s, 9H).

Compound 35C

Compound 35C was synthesized from compound 35B via Boc-deprotection in 4M HCl in dioxane following the procedure described in Example 28. LC/MS(m/z)=175 (M+H)⁺.

Example 35

Example 35 was synthesized from compound 26A and compound 35C viastandard peptide coupling reaction (see procedure in Example 23). HPLCRt (Method B): 5.550 min; LC/MS (m/z)=275 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ ppm 8.09-8.19 (m, 1H), 7.81-7.90 (m, 1H), 7.68-7.81 (m, 1H),7.17-7.37 (m, 3H), 6.99-7.17 (m, 2H), 6.65-6.83 (m, 1H), 4.04-4.20 (m,2H), 3.80-3.94 (m, 1H), 3.50-3.72 (m, 2H), 3.30-2.95 (m, 2H), 2.27-2.64(m, 5H), 2.08-2.19 (m, 1H), 1.93-2.08 (m, 1H), 1.73-1.92 (m, 3H), 1.67(d, J=13.6 Hz, 1H), 1.55 (br. s., 1H), 1.39-1.51 (m, 2H).

Example 36

Compound 36A. tert-Butyl3-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)azetidine-1-carboxylate

To a solution of 1-Boc-3-(hydroxyl)azetidine (250 mg, 1.443 mmol) in THF(3 mL) at 0° C., was added NaH (75 mg, 1.876 mmol) in portions. Themixture was stirred at 0° C. for 0.5 hour, then at RT for 0.5 hour. Tothe above mixture was added a solution of2-(Chloromethyl)-5-methyl-1,3,4-oxadiazole (191 mg, 1.443 mmol) in THF(3 mL) slowly. After stirring at RT overnight, the mixture was quenchedwith NH₄Cl (10 mL, saturated aqueous), then extracted with EtOAc (3×30mL). Combined organic layers were dried (MgSO₄), concentrated, andpurified via column chromatography (SiO₂, 0-70% EtOAc in n-hexane) toprovide compound 36A as colorless oil (100 mg, 25.7% yield). LC/MS(m/z)=270 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.60 (s, 2H), 4.29-4.39(m, 1H), 4.04-4.10 (m, 2H), 3.81 (dd, J=9.67, 4.39 Hz, 2H), 2.55 (s,3H), 1.38-1.42 (s, 9H).

Compound 36B. 2-((Azetidin-3-yloxy)methyl)-5-methyl-1,3,4-oxadiazolehydrochloride

Compound 36B was synthesized from compound 36A via Boc-deprotection in 4M HCl in dioxane followed the procedure described in Example 28. LC/MS(m/z)=170 (M+H)⁺.

Example 36

Example 36 was synthesized from compound 26A and compound 36B viastandard peptide coupling reaction (see procedure in Example 23). HPLCRt (Method B): 6.25 min; LC/MS (m/z)=438 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃)δ ppm 7.22-7.33 (m, 4H), 7.12-7.20 (m, 1H), 4.29-4.39 (m, 2H), 3.70-3.86(m, 3H), 3.42-3.53 (m, 1H), 2.97-3.05 (m, 0.5H), 2.80-2.93 (m, 1H), 2.70(dd, J=9.9, 3.3 Hz, 0.5H), 2.19-2.62 (m, 9H), 2.11 (d, J=13.7 Hz, 1H),1.77-2.04 (m, 4H), 1.60-1.72 (m, 2H), 1.49-1.60 (m, 1H), 1.44 (dd, 1H).

Example 37

Compound 37A

Compound 37A was synthesized from 2-adamantane carboxylic acid viadirect α-alkylation by following the procedure described in Example 5.Alternatively, compound 37A was synthesized via stepwise proceduresdescribed by Scheffer, John R. (Journal of the American ChemicalSociety, 126(11):3511-3520 (2004)). LC-MS (m/z)=303 (M−H)⁻.

Example 37

Compound 37A (15 mg, 0.05 mmol) in SOCl₂ (0.5 ml) was heated at 60° C.under Ar overnight. Excess SOCl₂ was evaporated off under reducedpressure to provide the corresponding acid chloride as a yellow oil. Toa solution of above acid chloride in CH₂Cl₂ (2.0 mL) was added Et₃N (15mg, 0.15 mmol), followed by 3-hydroxyazetidine (8.0 mg, 0.075 mmol). Themixture was stirred at RT overnight. Solvent was evaporated. The residuewas purified via Prep HPLC to provide Example 37 as a white solid (13mg, 72% yield). HPLC Rt (Method A): 6.80 min; LC/MS (m/z)=360 (M+H)⁺. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.11-7.45 (m, 4H), 4.15-4.42 (m, 1H),4.01-4.15 (m, 1H), 3.97 (s, 2H), 3.63-3.79 (m, 2H), 3.44-3.64 (m, 3H),3.15-3.30 (m, 1H), 2.81 (t, J=14.29 Hz, 2H), 2.63-2.73 (m, 1H),2.38-2.59 (m, 2H), 2.33 (s, 2H), 2.10 (dd, J=29.41, 13.47 Hz, 3H),1.59-1.97 (m, 2H).

Example 38

Compound 38A

A mixture of compound 25A (1.84 g, 8.84 mmol), malononitrile (0.561 mL,8.84 mmol), and ammonium acetate (0.068 g, 0.884 mmol) in EtOH (110 mL)was stirred at room temperature under argon for 6 hours. Afterevaporating the solvent, the residue was purified via columnchromatography (SiO₂, 0-60% EtOAc in n-hexane) to provide compound 38A(2.01 g, 89% yield) as a white solid. LC/MS (m/z)=257 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃): δ ppm 4.00 (s, 4H), 3.17 (br. s., 2H), 2.37 (br. s.,2H), 2.34 (br. s., 2H), 1.93 (br. s., 2H), 1.82 (br. s., 2H), 1.79 (br.s., 2H).

Compound 38B

To a solution of 3-chlorobenzylmagnesium chloride (7.02 mL, 1.756 mmol)in THF (10 mL) at −5° C. under argon was added a solution of compound38A (150 mg, 0.585 mmol) in THF (20 mL) dropwise while maintaining thetemperature below 0° C. After stirring at this temperature foradditional 1 hour, the mixture was warmed to room temperature over aperiod of 1 hour. The mixture was then diluted with saturated NH₄Cl (50mL) and extracted with ethyl acetate (50 mL). The organic layer waswashed (brine), dried (Na₂SO₄), filtered and concentrated. The residuewas purified via Prep HPLC provide compound 38B (200 mg, 0.522 mmol, 89%yield) as a white solid. LC/MS (m/z)=383 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃): δ ppm 7.37-7.27 (m, 4H), 4.55 (s, 1H), 3.97 (s, 4H), 3.21 (s,2H), 2.23-2.34 (m, 2H), 2.06-2.18 (m, 4H), 2.01 (br. s., 2H), 1.93 (br.s., 1H), 1.83 (br. s., 1H), 1.70 (br. s., 1H), 1.67 (br. s., 1H).

Compound 38C

A mixture of compound 38B (160 mg, 0.418 mmol), KOH (258 mg, 4.60 mmol),and ethylene glycol (2 mL) was placed in a 10 mL sealed tube reactor andheated at 205° C. oil bath for 18 hours. The mixture was cooled to roomtemperature, diluted with a solution of citric acid (50 mL, 10% w/v) andextracted with EtOAc (3×25 mL). The organic layer was washed (brine),dried (Na₂SO₄), filtered and concentrated. The residue was then dilutedwith HCl (aqueous, 10 mL, 2.0 M) and THF (10 mL) and heated at 60° C.for 6 hours. The THF was concentrated and the remaining aqueous phasewas diluted with brine and extracted with ethyl acetate. The organiclayer was washed (brine), dried (Na₂SO₄), filtered and concentrated. Theresidue was then dissolved in MeOH (20 mL) and sodium borohydride (47.4mg, 1.25 mmol) was added in portions. The mixture was stirred for 1 hourand quenched with aqueous HCl (5 mL). The solvent was concentrated andthe residue was purified via Prep HPLC (Gradient Solvent System: From50% A: 50% B to 0% A: 100% B; [A=10% MeOH/90% H₂O+0.1% TFA]; [B=90%MeOH/10% H₂O+0.1% TFA]; detection at 220 nm: 10 min gradient; PhenomenexLuna AXIA 30×100 mm) to provide compound 38C (73 mg, 50% yield) as anoff-white solid. LC/MS (m/z)=333 (M−H)⁻. ¹H NMR (400 MHz, CDCl₃) δ ppm7.24-7.33 (m, 2H), 7.14-7.23 (m, 2H), 3.79-3.89 (m, 1H), 3.07-3.24 (m,2H), 2.50 (d, J=7.03 Hz, 2H), 2.41-2.48 (m, 1H), 2.17 (dd, J=14.06, 3.52Hz, 1H), 2.10 (d, J=2.64 Hz, 1H), 2.04 (dd, J=14.06, 2.20 Hz, 1H), 1.99(br. s., 1H), 1.90 (br. s., 1H), 1.82 (d, J=14.50 Hz, 1H), 1.76 (br. s.,1H), 1.71 (br. s., 1H), 1.53-1.67 (m, 3H).

Alternatively, compound 38C was synthesized via the stepwise proceduresdescribed in Example 25.

Example 38

Example 38 was synthesized from compound 38C and 3-hydroxyazetidinehydrochloride via standard peptide coupling reaction (see procedure inExample 23). 38: white solid; Yield 23%. HPLC Rt (Method C): 6.380 min;LC/MS (m/z)=390 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.20 (br. s.,2H), 7.14 (br. s., 1H), 7.06 (br. s., 1H), 4.59 (d, J=3.52 Hz, 1H), 4.27(br. s., 1H), 3.76-3.93 (m, 3H), 3.49-3.66 (m, 1H), 3.05-3.33 (m, 2H),2.40 (d, J=9.67 Hz, 1H), 2.27 (br. s., 3H), 1.93-2.16 (m, 5H), 1.82-1.91(m, 2H), 1.69 (t, J=11.42 Hz, 1H), 1.58 (t, J=12.08 Hz, 2H).

Examples 39 to 386

Examples 39 to 386 in Table 1 were synthesized according to theprocedures described in Examples 1 to 38, the schemes, or by othersimilar methods known to one skilled in the art, with other appropriatereagents. In the structures set forth in Table 1, the “—O” attached toan adjacent carbon atom substituted with ═O is used to denote an “—OH”group. Similarly, in the structures set forth in Table 1, the “N”attached to an adjacent carbon atom substituted with ═O is used todenote an “NH” moiety. The compounds set forth in Table 1 below areracemic, achiral or diastereomeric unless indicated to the contrary.

TABLE 1 LC/MS Mass HPLC Example Structure [(M − H)⁻/(M + H)⁺] purity (%) 39

283 94.8  40

287 >95  41

313 >98  42

299 99  43

299 >97  44

275 >95  45

283 96  46

303 98.5  47

294 95.6  48

294 98  49

271 90  50

247 95  51

291 96  52

261 97  53

277 >90  54

303 >92  55

354 >99  56

366 96.7  57

366 95.7  58

345 94.9  59

301 96.8  60

317 >95  61 (chiral)

366 >95  62 (chiral)

366 95  63

303 >95  64

317 >95  65

331 >95  66

357 >95.6  67

343 >98  68

299 97  69

317 99.6  70

299 95  71

346 98  72

308 98.8  73

362 92.5  74

362 96.3  75

333 96.2  76

299 95  77

333 98.4  78

314 96  79

372 96.2  80

328 98  81

372 98  82

358 98  83

364 98  84

422 98  85

342 96  86

358 98  87

358 98  88

358 97.2  89

372 95  90

401 96  91

344 96.3  92

356 98  93

360 97  94

360 88  95

360 96  96

374 95  97

374 97  98

400 98  99

360 96.3 100

374 97.3 101

374 97.5 102 (chiral)

374 96.4 103 (chiral)

374 96.2 104

340 >96 105

368 96.8 106

451 97.4 107

388 99.4 108

388 98 109

353 98 110

369 98 111

385 98 112

360 98 113

383 97 114

374 96 115

369 97 116

374 98 117

400 95 118

414 96 119

351 98 120

360 95 121

356 98 122

356 98 123

299 95 124

297 >96 125

291 98.3 126

305 91 127

305 91 128

402 98.8 129

218 >90 130 (chiral)

319 99 131 (chiral)

319 99 132

287 98 133

287 97.2 134

273 98.2 135

289 >95 136

283 97 137

291 >95 138

275 >95 139

277 >98 140

288 98 141

301 98 142

317 >97 143

362 >92 144

319 98.1 145

317 97.8 146

333 99.3 147

333 >98 148

335 96 149 (chiral)

285 99 150

303 >97 151 (chiral)

299 98 152 (chiral)

303 98 153 (chiral)

299 98 154 (chiral)

303 98 155

299 >92 156

315 95.6 157

333 95.2 158

333 98.7 159 (chiral)

327 99 160 (chiral)

327 99 161

315 98 162

348 98 163

362 98 164

362 97 165

436 96 166

390 95 167

390 98.1 168

374 97.9 169

356 >96 170

304 98 171

354 >97 172

358 98 173

364 95 174

420 98 175

457 95 176

477 98 177

344 97 178

471 97.7 179

348 98 180

334 95 181

388 95 182

446 95 183

413 95 184

384 95 185

439 95 186

462 95 187

493 97 188

358 98 189

460 98 190

388 97 191

359 98 192

417 97 193

437 97.9 194

417 95 195

433 >95 196

388 >95 197

387 >95 198

383 >95 199

387 98 200

417 >95 201

417 98 202

369 95 203

374 95.3 204

399 98 205

399 >95 206

419 99 207

374 95 208

400 >96 209

342 97 210

444 96 211

390 >97 212

398 >97.3 213

374 98 214

390 98 215

376 >95 216

413 98 217 (chiral)

360 92 218

425 97 219

431 97 220

367 99 221

431 98 222

427 98 223

394 97.9 224

413 97 225

330 94 226

344 98 227 (chiral)

417 92 228 (chiral)

417 92 229

363 96 230 (chiral)

417 98 231

413 95 232 (chiral)

417 98 233

360 97 234

387 99 235

403 >97 236

403 95 237

397 96 238 (chiral)

342 >95 239

408 >95 240

417 95 241 (chiral)

399 98 242 (chiral)

399 97 243

457 95 244

360 97 245

417 98 246 (chiral)

356 96 247

358 97 248 (chiral)

408 >95 249

408 97 250

447 98 251

404 95 252

346 98 253

388 >95 254

390 >95 255

350 92 256 (chiral)

351 97 257

374 95.4 258 (chiral)

426 >98.6 259 (chiral)

467 98 260 (chiral)

399 97 261

405 97 262

356 99 263

330 96 264

387 98 265 (chiral)

356 96 266

376 99 267

387 95 268 (chiral)

358 90 269

330 95 270 (chiral)

358 95 271

362 95 272

374 98 273 (chiral)

356 98 274 (chiral)

370 97 275 (chiral)

356 >95 276

344 96 277 (chiral)

369 98 278 (chiral)

383 95 279 (chiral)

370 >96 280

418 >95 281 (chiral)

370 98 282 (chiral)

427 97 283

356 98 284 (chiral)

376 >99 285 (chiral)

376 >99 286

390 98.7 287

390 99.3 288 (chiral)

360 95 289 (chiral)

356 98 290 (chiral)

356 98 291 (chiral)

360 95 292

384 98 293

374 97.3 294

372 95 295 (chiral)

356 100 296 (chiral)

377 97.9 297 (chiral)

356 100 298

362 95 299

372 95.5 300

372 95.6 301

341 98 302 (chiral)

358 97 303

448 98 304

346 96 305

490 98 306

324 >98 307

362 93 308

328 97 309

283 99 310

331 98 311

330 98 312

381 94.2 313

399 98.3 314

399 97.8 315

406 99.3 316

444 99.0 317

377 100.0 318

430 100.0 319

356 91.7 320

343 99.2 321

404 99.2 322

392 100.0 323

358 100.0 324

402 95.3 325

342 91.2 326

465 97.9 327

446 90.9 328

342 97.1 329

459 100.0 330

432 98.4 331

397 96.4 332

370 97.0 333

404 100.0 334

390 100.0 335

433 98.4 336

411 100.0 337

449 99.1 338

394 97.9 339

370 97.5 340

390 95.5 341

469 98.3 342

433 99.3 343

394 100.0 344

377 100.0 345

384 99.3 346

369 100.0 347

325 100.0 348

330 100.0 349

431 96.4 350

406 98.9 351

344 96.5 352

371 100.0 353

390 100.0 354

402 100.0 355

340 97.2 356 (chiral)

457 99 357 (chiral)

358 96 358

387 96 359

390 99 360

376 97 361

374 99 362

383 99 363

399 96 364

419 100 365

460 100 366

460 100 367

376 100 368

342 100 369

357 99.3 370

413 98.6 371

399 100 372

328 99.1 373

356 100 374

465 100 375

465 100 376

358 100 377

371 100 378

444 100 379

384 100 380

445 99.3 381

459 100 382

425 100 383

370 98.3 384

454 99.5 385

420 98 386

388 97

Assay(s) for 11-Beta-Hydroxysteroid Dehydrogenase Activity

The in vitro inhibition of recombinant human 11beta-HSD1 was determinedas follows.

[³H]-Cortisone with a specific radioactivity of 50 Ci/mmol (ART 743,Lot: 050906) was from American Radiolabeled Chemicals, Inc. (St Louis,Mo.); monoclonal ab to Cortisol (P01-9294M-P, Lot: L-28) was from EastCoast Bio., (North Berwick, Me.); Protein A-yttrium silicate, type-1,SPA bead NJ® (RPN-143) was from Amersham LifeSciences, (Piscataway,N.J.); 384 well-Optiplate384 (#6007299) was from PerkinElmer (Boston,Mass.); DPBS, pH 7.4 (14040) is from GIBCO, (Grand Island, N.Y.);carbenoxolone (C4790) is from Sigma, (St Louis, Mo.).

Full length recombinant human 11β-HSD-1 cDNAs and the cDNA encodinghuman 11β-HSD-2 were expressed stably in HEK 293 EBNA cells. Cells weregrown in DMEM (high glucose) containing MEM non-essential amino acids,L-glutamine, hygromycin B (200 μg/ml), and G-418(200 μg/ml) in thepresence of 10% FBS.

Human 11β-HSD-1 transfected HEK 293 EBNA cells were grown to 80%confluency and the cell pellet was quick frozen and stored at −80° C.before purification. Cell paste, 40 g from −80° C. storage, was thawedin water and then 100 ml of homogenization buffer H (0.01 M sodiumphosphate pH 6.5 containing 0.25 M sucrose and protease inhibitorcocktail (Roche #1836145 1 tablet per 50 ml) were added to completelythaw the paste. The cell paste suspension was homogenized using aPolytron for 20 seconds to create a homogeneous mixture. Additionalbuffer H was added to a volume of 300 ml and cells were broken openusing a N2-bomb (at 4° C.) in two batches by treating at 500 psi. Theextract was centrifuged at 750×g for 30 min. The supernatant wascentrifuged at 20,000×g for 30 min. The supernatant was furthercentrifuged at 105,000×g for 60 min. The 105,000×g pellet wasresuspended in buffer H and centrifuged at 105,000×g for 60 min. Themicrosome pellet was scraped from the bottom of tube and resuspended in0.01M phosphate buffer, pH 6.5 containing protease inhibitors (Roche#1836145, 1 tablet per 50 ml). Aliquots were stored at −80° C. untilneeded. The protein concentration was measured by the BioRad methodusing BSA standard.

Compounds were dissolved in DMSO to obtain 10 mM stock concentrations.From the 10 mM stock, the compounds were diluted in DMSO to achieve theconcentrations.

11β-HSD-1 SPA Enzyme Assay

11β-HSD-1 was assayed by Scintillation Proximity assay in a 384-wellPerkin Elmer white plate. The dose response of the compounds wasdetermined using 11 half-log dilutions of compound in DMSO in duplicate.To each well, 0.5 μl of compound dilution in DMSO were added. 15 μl ofassay buffer (for blanks) or 15 μl of human microsomes in assay bufferwere added next and the plates were incubated for 10 min at roomtemperature. The final microsomal protein concentration was 1.1μg/assay. Duplicates were in the same plate one row below the other. 10μl of ³H-cortisone (final concentration 40 nM) was added to each welland the plate was spun down to mix and bring down the contents to thebottom of the wells. The plates were incubated at room temperature withgentle shaking for 4 hrs. The reaction was stopped with addition of 10μl of 10 mM carbenoxolone. Then, 0.5 mg of yttrium silicate SPA beadscoupled to anti-cortisol antibody in 20 μl were added to all the wellsof plate, which were spun down once more and incubated at roomtemperature overnight. The plate was read in a TopCount® (1 min/well).Data were uploaded automatically to Tool Set, a Lead Evaluationinformatics program for data capture and calculation. Graphs weregenerated with the Curve Master program.

Compounds of the present invention were tested in the assay describedimmediately above and the results shown in the Table 2 below wereobtained.

TABLE 2 h HSD1 Example Structure IC50 (nM) 4

234 8

633 20

10000 22

159 23

8.3 25

8.5 26

2.9 27

12 28

10 31

2.0 32

21 34

196 35

636 36

14 37

15 39

24 44

3.0 49

97 55

2982 64

21 79

81 98

1.6 103

10 106

457 117

90 122

253 124

2.2 126

13 127

14 132

15 134

30 136

1152 140

651 164

2.3 167

20 174

1.0 181

128 182

2.4 183

182 188

121 190

9121 195

105 199

6.9 210

316 212

127 213

44 216

5.1 235

520 236

274 240

67 242

8.8 243

16 247

3.0 250

1724 259

75 265

6.1 270

16 277

10000 279

260 281

175 292

2.8 301

0.3 302

2.4 303

4.7 304

25 305

28 306

30 307

383 308

10000

The in vivo inhibition of recombinant human 11beta-HSD1 was determinedas follows.

Studies were conducted utilizing diet induced obese (DIO) mice obtainedfrom Jackson Laboratory (ME, USA). These mice were fed a 60% fat diet(Research Diets D12492) soon after weaning and kept on this diet for 24weeks. These mice were individually housed. All mice were housed undercontrolled temperature (23° C.) and lighting (12 hours of light between6 am to 6 pm, 12 hours of dark) with free access to water. The animalscontinued on this diet and were utilized for experimentation at 30 to 32weeks of age, at which time these mice weighed 45 to 55 grams.

The basic model of 11-dehydrocorticosterone (DHC) administration to miceto produce corticosterone has been reported in the literature forclinical and preclinical evaluation of the activity of 11 β HSD.Essentially DHC (Steraloids INC, Newport R.I.), was suspended in thevehicle at a concentration of 10 mg/kg in a volume of 7.5 ml/kg of mousebody weight. For a typical study, non-fasting mice were weighed andseparated into groups (n=6) where body weights are not statisticallydifferent from each other. Animals were bled via a tail knick, for a 0time sample and then dosed orally (7.5 ml/kg) with vehicle or drug. At60 minutes post administration of vehicle or compound, mice were bledagain via the tail tip and dosed orally (7.5 ml/kg) with DHC 10 mg/kg.All animals were subsequently bled at 30, 60 and 120 minutes post DHCdosing. Thirty-five microliters of whole blood are collected per timepoint in microvette tubes coated with EDTA (Sarstedt Tubes Microvette CB300/Haematology Potassium EDTA # 16.444.300) and kept on ice. Sampleswere centrifuged at 4° C. in a Beckman Coulter centrifuge for 10 minutesat 2500 RPM. Plasma was separated and collected and immediately frozenat −20° C. until corticosterone analysis could be assessed.

Plasma Corticosterone was measured using an EIA (IDS AC-14F1). Sampleswere measured at (1:2) for the −30 (or −60 minute) and 0 time point and(1:10) for the 30, 60 and 120 minutes time points. AUC was calculatedusing Graphpad and the zero timepoint was used as the baseline. One wayANOVA was calculated using Sigmastat. A p value of less that 0.05 viapost hoc analysis with Dunnett's was used to determine statisticalsignificance.

The vehicle utilized for the suspension of the compounds was 0.5%methocel; 0.1% tween 80 in water. Methocel Cellulose (M-0262) waspurchased from Sigma-Aldrich, St Louis, Mo. 6. Tween 80 (274364) waspurchased from Sigma-Aldrich, St Louis, Mo. Compounds were administeredin 7.5 ml/kg volumes at final dosages of 0.1 to 300 mg/kg depending onthe study and compound evaluated.

Compounds of the present invention were tested in the assay describedimmediately above and the results shown in the Table 3 below wereobtained.

TABLE 3 Example Dose % inhibition 25 30 mpK 74 26 30 mpK 57 217 30 mpK67 242 30 mpK 65

Utilities and Combinations

A. Utilities

The compounds of the present invention possess activity as inhibitors ofthe enzyme 11-beta-hydroxysteroid dehydrogenase type I, and, therefore,may be used in the treatment of diseases associated with11-beta-hydroxysteroid dehydrogenase type I activity. Via the inhibitionof 11-beta-hydroxysteroid dehydrogenase type I, the compounds of thepresent invention may preferably be employed to inhibit or modulateglucocorticoid production, thereby interrupting or modulating cortisoneor cortisol production.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, delayed wound healing, atherosclerosis and itssequelae (acute coronary syndrome, myocardial infarction, anginapectoris, peripheral vascular disease, intermittent claudication),abnormal heart function, myocardial ischemia, stroke, MetabolicSyndrome, hypertension, obesity, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy, glaucoma and inflammatory diseases, such as, rheumatoidarthritis, Cushing's Disease, Alzheimer's Disease and osteoarthritis.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am.Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med.Chem.—Imm., Endoc. & Metab. Agents, 1:1-24 (2001).

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other 11-beta-hydroxysteroid dehydrogenase type I inhibitors or oneor more other suitable therapeutic agents useful in the treatment of theaforementioned disorders including: anti-diabetic agents,anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-atherosclerotic agents, anti-ischemic agents,anti-hypertensive agents, anti-obesity agents, anti-dislipidemic agents,anti-dyslipidemic agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,appetite suppressants, memory enhancing agents, cognition promotingagents and anti-inflammatory agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include insulin and insulinanalogs: LysPro insulin, inhaled formulations comprising insulin;glucagon-like peptides; sulfonylureas and analogs: chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide,glyburide, glimepiride, repaglinide, meglitinide; biguanides: metformin,phenformin, buformin; alpha2-antagonists and imidazolines: midaglizole,isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan; other insulinsecretagogues: linogliride, insulinotropin, exendin-4, BTS-67582,A-4166; thiazolidinediones: ciglitazone, pioglitazone, troglitazone,rosiglitazone; PPAR-gamma agonists; PPAR-alpha agonists; PPARalpha/gamma dual agonists; SGLT2 inhibitors; dipeptidyl peptidase-IV(DPP4) inhibitors; glucagon-like peptide-1 (GLP-1) receptor agonists;aldose reductase inhibitors; RXR agonists: JTT-501, MCC-555, MX-6054,DRF2593, GI-262570, KRP-297, LG100268; fatty acid oxidation inhibitors:clomoxir, etomoxir; α-glucosidase inhibitors: precose, acarbose,miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945;beta-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243,TAK-667, AZ40140; phosphodiesterase inhibitors, both cAMP and cGMP type:sildenafil, L686398: L-386,398; amylin antagonists: pramlintide, AC-137;lipoxygenase inhibitors: masoprocal; somatostatin analogs: BM-23014,seglitide, octreotide; glucagon antagonists: BAY 276-9955; insulinsignaling agonists, insulin mimetics, PTP1B inhibitors: L-783281,TER17411, TER17529; gluconeogenesis inhibitors: GP3034; somatostatinanalogs and antagonists; antilipolytic agents: nicotinic acid, acipimox,WAG 994; glucose transport stimulating agents: BM-130795; glucosesynthase kinase inhibitors: lithium chloride, CT98014, CT98023; andgalanin receptor agonists.

Other suitable thiazolidinediones include Mitsubishi's MCC-555(disclosed in U.S. Pat. No. 5,594,016), Glaxo-Wellcome's GL-262570,englitazone (CP-68722, Pfizer), or darglitazone (CP-86325, Pfizer,isaglitazone (MIT/J&J), JTT-501 (JPNT/P&U), L-895645 (Merck), R-119702(Sankyo/WL), N,N-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi).

Suitable PPAR alpha/gamma dual agonists include AR-HO39242(Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck), aswell as those disclosed by Murakami et al., “A Novel Insulin SensitizerActs As a Coligand for Peroxisome Proliferation—Activated Receptor Alpha(PPAR alpha) and PPAR gamma; Effect of PPAR alpha Activation on AbnormalLipid Metabolism in Liver of Zucker Fatty Rats”, Diabetes, 47:1841-1847(1998), and WO 01/21602, the disclosure of which is incorporated hereinby reference, employing dosages as set out therein, which compoundsdesignated as preferred are preferred for use herein.

Suitable alpha2 antagonists also include those disclosed in WO 00/59506,employing dosages as set out herein.

Suitable SGLT2 inhibitors include T-1095, phlorizin, WAY-123783, andthose described in WO 01/27128.

Suitable DPP4 inhibitors include saxagliptan, sitagliptan, vildagliptan,and denagliptan.

Suitable aldose reductase inhibitors include those disclosed in WO99/26659.

Suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

Examples of glucagon-like peptide-1 (GLP-1) receptor agonists includeExenatide (Byetta™), NN2211 (Liraglutide, Novo Nordisk), AVE0010(Sanofi-Aventis), R1583 (Roche/Ipsen), SUN E7001 (Daiichi/Santory),GSK-716155 (GSK/Human Genome Sciences) and Exendin-4 (PC-DAC™).

Other anti-diabetic agents that can be used in combination withcompounds of the invention include ergoset and D-chiroinositol.

Suitable anti-ischemic agents include, but are not limited to, thosedescribed in the Physician's Desk Reference and NHE inhibitors,including those disclosed in WO 99/43663.

Examples of suitable lipid lowering agents for use in combination withthe compounds of the present invention include one or more MTPinhibitors, HMG CoA reductase inhibitors, squalene synthetaseinhibitors, fibric acid derivatives, ACAT inhibitors, lipoxygenaseinhibitors, cholesterol absorption inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, upregulators of LDL receptor activity, bileacid sequestrants, cholesterol ester transfer protein inhibitors (e.g.,CP-529414 (Pfizer)), and/or nicotinic acid and derivatives thereof.

MTP inhibitors which may be employed as described above include thosedisclosed in U.S. Pat. No. 5,595,872, U.S. Pat. No. 5,739,135, U.S. Pat.No. 5,712,279, U.S. Pat. No. 5,760,246, U.S. Pat. No. 5,827,875, U.S.Pat. No. 5,885,983, and U.S. Pat. No. 5,962,440.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compounds of formula I include mevastatin and relatedcompounds, as disclosed in U.S. Pat. No. 3,983,140, lovastatin,(mevinolin) and related compounds, as disclosed in U.S. Pat. No.4,231,938, pravastatin, and related compounds, such as disclosed in U.S.Pat. No. 4,346,227, simvastatin, and related compounds, as disclosed inU.S. Pat. Nos. 4,448,784 and 4,450,171. Other HMG CoA reductaseinhibitors which may be employed herein include, but are not limited to,fluvastatin, disclosed in U.S. Pat. No. 5,354,772; cerivastatin, asdisclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080; atorvastatin, asdisclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and5,686,104; atavastatin (Nissan/Sankyo's nisvastatin (NK-104)), asdisclosed in U.S. Pat. No. 5,011,930; visastatin (Shionogi-Astra/Zeneca(ZD-4522)) as disclosed in U.S. Pat. No. 5,260,440.

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin, and ZD-4522.

The fibric acid derivatives which may be employed in combination withone or more compounds of formula I include fenofibrate, gemfibrozil,clofibrate, bezafibrate, ciprofibrate, clinofibrate, and the like,probucol, and related compounds, as disclosed in U.S. Pat. No.3,674,836, fenofibrate and gemfibrozil being preferred, bile acidsequestrants, such as cholestyramine, colestipol and DEAE-Sephadex(Secholex®, Policexide®), as well as lipostabil (Rhone-Poulenc), EisaiE-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402),tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche),aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulenederivative), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinicacid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin,poly(diallylmethylamine) derivatives, such as disclosed in U.S. Pat. No.4,759,923, quaternary amine poly(diallyldimethylammonium chloride) andionenes, such as disclosed in U.S. Pat. No. 4,027,009, and other knownserum cholesterol lowering agents.

The ACAT inhibitor which may be employed in combination with one or morecompounds of formula I include those disclosed in Drugs of the Future24:9-15 (1999), (Avasimibe); “The ACAT inhibitor, Cl-1011 is effectivein the prevention and regression of aortic fatty streak area inhamsters”, Nicolosi et al., Atherosclerosis (Shannon, Irel).,137(1):77-85 (1998); “The pharmacological profile of FCE 27677: a novelACAT inhibitor with potent hypolipidemic activity mediated by selectivesuppression of the hepatic secretion of ApoB 100-containinglipoprotein”, Ghiselli, Giancarlo, Cardiovasc. Drug Rev., 16(1):16-30(1998); “RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACATinhibitor”, Smith, C. et al., Bioorg. Med. Chem. Lett., 6(1):47-50(1996); “ACAT inhibitors: physiologic mechanisms for hypolipidemic andanti-atherosclerotic activities in experimental animals”, Krause et al,Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A.,Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, BocaRaton, Fla.; “ACAT inhibitors: potential anti-atherosclerotic agents”,Sliskovic et al., Curr. Med. Chem., 1(3), 204-25 (1994); “Inhibitors ofacyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemicagents. 6. The first water-soluble ACAT inhibitor with lipid-regulatingactivity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7.Development of a series of substitutedN-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity”, Stout et al., Chemtracts: Org. Chem.,8(6):359-62 (1995), or TS-962 (Taisho Pharmaceutical Co. Ltd.).

The hypolipidemic agent may be an upregulator of LDL receptor activity,such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).

Examples of suitable cholesterol absorption inhibitors for use incombination with the compounds of the invention include ezetimibe(Zetia®).

Examples of suitable ileal Na⁺/bile acid cotransporter inhibitors foruse in combination with the compounds of the invention include compoundsas disclosed in Drugs of the Future, 24:425-430 (1999).

The lipoxygenase inhibitors which may be employed in combination withone or more compounds of formula I include 15-lipoxygenase (15-LO)inhibitors, such as benzimidazole derivatives, as disclosed in WO97/12615, 15-LO inhibitors, as disclosed in WO 97/12613, isothiazolones,as disclosed in WO 96/38144, and 15-LO inhibitors, as disclosed bySendobry et al., “Attenuation of diet-induced atherosclerosis in rabbitswith a highly selective 15-lipoxygenase inhibitor lacking significantantioxidant properties”, Brit. J. Pharmacology, 120:1199-1206 (1997),and Cornicelli et al., “15-Lipoxygenase and its Inhibition: A NovelTherapeutic Target for Vascular Disease”, Current Pharmaceutical Design,5:11-20 (1999).

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g. diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors (e.g., aliskiren), ACE inhibitors(e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril,cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1receptor antagonists (e.g., losartan, irbesartan, valsartan), ETreceptor antagonists (e.g., sitaxsentan, atrsentan, and compoundsdisclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AIIantagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a cannabinoid receptor 1antagonist or inverse agonist, a beta 3 adrenergic agonist, a lipaseinhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroidreceptor beta drug, and/or an anorectic agent.

Cannabinoid receptor 1 antagonists and inverse agonists which may beoptionally employed in combination with compounds of the presentinvention include rimonabant, SLV 319, CP-945598 (Pfizer), SR-147778(Sanofi-Aventis), MK0364 (Merck) and those discussed in D. L. Hertzog,Expert Opin. Ther. Patents, 14:1435-1452 (2004).

The beta 3 adrenergic agonists which may be optionally employed incombination with compounds of the present invention include AJ9677(Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other knownbeta 3 agonists, as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615,5,491,134, 5,776,983, and 5,488,064, with AJ9677, L750,355, and CP331648being preferred.

Examples of lipase inhibitors which may be optionally employed incombination with compounds of the present invention include orlistat orATL-962 (Alizyme), with orlistat being preferred.

The serotonin (and dopamine) reuptake inhibitor and/or modulator whichmay be optionally employed in combination with a compound of formula Imay be sibutramine, topiramate (Johnson & Johnson), APD-356 (Arena) oraxokine (Regeneron), with sibutramine and APD-356 being preferred.

Examples of thyroid receptor beta compounds which may be optionallyemployed in combination with compounds of the present invention includethyroid receptor ligands, such as those disclosed in WO 97/21993 (U. CalSF), WO 99/00353 (KaroBio), and WO 00/039077 (KaroBio), with compoundsof the KaroBio applications being preferred.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine, or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds ofthe present invention include CCK receptor agonists (e.g., SR-27895B);MCHR1 antagonist (e.g., GSK 856464); galanin receptor antagonists; MCR-4antagonists (e.g., HP-228); leptin or mimetics; urocortin mimetics, CRFantagonists, and CRF binding proteins (e.g., RU-486, urocortin).

Further, the compounds of the present invention may be used incombination with HIV protease inhibitors, including but not limited toReyataz® and Kaletra®.

Examples of suitable memory enhancing agents, anti-dementia agents, orcognition promoting agents for use in combination with the compounds ofthe present invention include, but are not limited to, donepezil,rivastigmine, galantamine, memantine, tacrine, metrifonate, muscarine,xanomelline, deprenyl and physostigmine.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include, but are not limitedto, prednisone, acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha,prednisolone, methylprednisolone, dexamethazone, flucatisone,betamethasone, hydrocortisone and beclomethasone.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

The compounds of formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection, or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents.

In carrying out the method of the invention for treating diabetes andrelated diseases, a pharmaceutical composition will be employedcontaining the compounds of formula I, with or without otherantidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or othertype therapeutic agents in association with a pharmaceutical vehicle ordiluent. The pharmaceutical composition can be formulated employingconventional solid or liquid vehicles or diluents and pharmaceuticaladditives of a type appropriate to the mode of desired administration,such as pharmaceutically acceptable carriers, excipients, binders, andthe like. The compounds can be administered to a mammalian patient,including humans, monkeys, dogs, etc. by an oral route, for example, inthe form of tablets, capsules, beads, granules or powders. The dose foradults is preferably between 1 and 2,000 mg per day, which can beadministered in a single dose or in the form of individual doses from1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

1. A compound of formula (I)

enantiomers, diastereomers, solvates, or salts thereof wherein: A is

 which is substituted with at least one R₄ other than hydrogen; or

 which may be optionally substituted with one or more R₄'s; X is—C(═O)OH, —C(═O)C(═O)OH, —C(═O)NR₉R₉, tetrazolyl, or —C(═O)NHS(O)₂R₉; Wis absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O—,(—CR_(8a)R_(8b)—)_(m)—N(R₁₄)—, C₃₋₆ cycloalkyl, alkenyl or alkynyl,wherein the cycloalkyl or alkenyl may be optionally substituted with oneor more R_(8a)'s; m is 1-3; Z is —CN, C₃₋₁₀ alkyl, cycloalkyl, aryl orarylalkyl, all of which may be optionally substituted with one or moreR₄'s; provided that W and Z, or when W is absent, X and Z, are attachedto the same carbon on Ring A; R₄, at each occurrence, is independentlyselected from hydrogen, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, halo,═O, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH,—SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(O)R₁₀,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀,—NR₉C(═O)OR₈ or —NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynylor cycloalkyl may be optionally substituted with one or more R₅'s; R₅,at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halo,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀,—NR₉C(═O)OR₈ or —NR₉S(O₂)R₈; R₈, at each occurrence, is independentlyalkyl, aryl or heterocyclyl; R_(8a), at each occurrence, isindependently hydrogen, alkyl or aryl; R_(8b), at each occurrence, isindependently hydrogen, —C(═O)OH, alkyl, —OH, halo, —CN, —OR₁₀,—C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl may be optionallysubstituted with one or more R_(9a)'s; or R_(8a) and R_(8b) are takentogether with the carbon to which both are attached to form a 3- to7-membered ring, which may optionally contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with 0-3 R_(9a); R₉, ateach occurrence, is independently hydrogen, alkyl, alkoxy, cycloalkyl,aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may beoptionally substituted with 0-5 R_(9a), and the heterocyclyl orheterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S; ortwo R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s; R_(9a), ateach occurrence, is independently selected from alkyl, haloalkyl, aryl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄,—OCF₃, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —C(═NR₁₄)NR₁₄R₁₄, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄,—NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl, cycloalkyl,cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a); R₁₀, at each occurrence, is independentlyselected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a), and the heterocyclyl and heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; R_(10a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —C(═NR₁₄)NR₁₄R₁₄, —NHC(NR₁₄)NR₁₄R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ or arylalkyl; R₁₄, at each occurrence, isindependently selected from hydrogen, alkyl, cycloalkyl, aryl orarylalkyl, wherein the alkyl, cycloalkyl, aryl or arylalkyl may beoptionally substituted with 0-3 R_(14a); R_(14a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅,—C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃,—C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅,—C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅,—C(═NR₁₅)NR₁₅R₁₅, —NHC(NR₁₅)NR₁₅R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅,—NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ or arylalkyl; and R₁₅, at each occurrence,is independently selected from hydrogen, alkyl, cycloalkyl, aryl orarylalkyl.
 2. The compound of claim 1, wherein the

is substituted with at least one R₄ other than hydrogen.
 3. The compoundof claim 1, wherein: X is —C(═O)OH, —C(═O)C(═O)OH, —C(═O)NR₉R₉, ortetrazolyl; W is absent, (—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O—,(—CR_(8a)R_(8b))_(m)N(R₁₄)—, or alkenyl, wherein the alkenyl may beoptionally substituted with one or more R_(8a)'s; m is 1-3; Z is CN,C₃₋₁₀ alkyl, cycloalkyl, aryl or arylalkyl, all of which may beoptionally substituted with one or more R₄'s; provided that W and Z, orwhen W is absent, X and Z, are attached to the same carbon on Ring A;R₄, at each occurrence, is independently selected from hydrogen, alkyl,aryl, alkenyl, alkynyl, cycloalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl or cycloalkyl maybe optionally substituted with one or more R₅, at each occurrence, isindependently selected from hydrogen, alkyl, haloalkyl, aryl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈; R₈, at each occurrence, is independently alkyl, aryl orheterocyclyl; R_(8a), at each occurrence, is independently hydrogen,alkyl or aryl; R_(8b), at each occurrence, is independently hydrogen,—C(═O)OH, alkyl, —OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉,wherein the alkyl may be optionally substituted with one or moreR_(9a)'s; or R_(8a) and R_(8b) are taken together with the carbon towhich both are attached to form a 3- to 7-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with 0-3 R_(9a); R₉, at each occurrence, isindependently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-5 R_(9a), and the heterocyclyl or heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; or two R₉'s togetherwith the nitrogen to which they are attached form a unsaturated,saturated or partially saturated cyclic ring system containing from 2-10carbon atoms and from 0-4 additional heteroatoms selected from N, O, S,S(O) and S(O)₂, wherein said ring system may be optionally substitutedor fused with one or more R_(9a)'s; R_(9a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo, ═O,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀,—OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a); R₁₀, at each occurrence, isindependently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a), and the heterocyclyl andheterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl; R₁₄, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl, wherein the alkyl,cycloalkyl, aryl or arylalkyl may be optionally substituted with 0-3R_(14a); R_(14a), at each occurrence, is independently selected fromalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and R₁₅, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl.
 4. The compound of claim1, wherein: X is —C(O)OH, —C(═O)NR₉R₉, or tetrazolyl; W is absent,(—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O— or alkenyl, wherein thealkenyl may be optionally substituted with one or more R_(8a)'s; m is1-2; Z is CN, C₃₋₁₀ alkyl, cycloalkyl, aryl or arylalkyl, all of whichmay be optionally substituted with one or more R₄'s; provided that W andZ, or when W is absent, X and Z, are attached to the same carbon on RingA; R₄, at each occurrence, is independently selected from hydrogen,alkyl, aryl, alkenyl, alkynyl, cycloalkyl, halo, ═O, —NH₂, —CN, —NO₂,—C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(O)R₁₀, —NR₉C(O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl or cycloalkyl maybe optionally substituted with one or more R₅, at each occurrence, isindependently selected from hydrogen, alkyl, haloalkyl, aryl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈; R₈, at each occurrence, is independently alkyl, aryl orheterocyclyl; R_(8a), at each occurrence, is independently hydrogen,alkyl or aryl; R_(8b), at each occurrence, is independently hydrogen,—C(═O)OH, alkyl, —OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉,wherein the alkyl may be optionally substituted with one or moreR_(9a)'s; or R_(8a) and R_(8b) are taken together with the carbon towhich both are attached to form a 3- to 7-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with 0-3 R_(9a); R₉, at each occurrence, isindependently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-5 R_(9a), and the heterocyclyl or heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; or two R₉'s togetherwith the nitrogen to which they are attached form a unsaturated,saturated or partially saturated cyclic ring system containing from 2-10carbon atoms and from 0-4 additional heteroatoms selected from N, O, S,S(O) and S(O)₂, wherein said ring system may be optionally substitutedor fused with one or more R_(9a)'s; R_(9a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo, O,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀,—OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a); R₁₀, at each occurrence, isindependently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a), and the heterocyclyl andheterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl; R₁₄, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl, wherein the alkyl,cycloalkyl, aryl or arylalkyl may be optionally substituted with 0-3R_(14a); R_(14a), at each occurrence, is independently selected fromalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and R₁₅, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl.
 5. The compound of claim1, wherein: X is —C(O)OH, —C(═O)NR₉R₉, or tetrazolyl; W is absent,(—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O— or alkenyl, wherein thealkenyl may be optionally substituted with one or more R_(8a)'s; m is1-2; Z is cycloalkyl, aryl or arylalkyl, all of which may be optionallysubstituted with one or more R₄'s; provided that W and Z, or when W isabsent, X and Z, are attached to the same carbon on Ring A; R₄, at eachoccurrence, is independently selected from hydrogen, alkyl, aryl,alkenyl, alkynyl, cycloalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(O)OH,—C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(O)R₁₀, —NR₉C(O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl or cycloalkyl maybe optionally substituted with one or more R₅'s; R₅, at each occurrence,is independently selected from hydrogen, alkyl, haloalkyl, aryl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈; R₈, at each occurrence, is independently alkyl, aryl orheterocyclyl; R_(8a), at each occurrence, is independently hydrogen,alkyl or aryl; R_(8b), at each occurrence, is independently hydrogen,—C(═O)OH, alkyl, —OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉,wherein the alkyl may be optionally substituted with one or moreR_(9a)'s; or R_(8a) and R_(8b) are taken together with the carbon towhich both are attached to form a 3- to 7-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with 0-3 R_(9a); R₉, at each occurrence, isindependently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-5 R_(9a), and the heterocyclyl or heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; or two R₉'s togetherwith the nitrogen to which they are attached form a unsaturated,saturated or partially saturated cyclic ring system containing from 2-10carbon atoms and from 0-4 additional heteroatoms selected from N, O, S,S(O) and S(O)₂, wherein said ring system may be optionally substitutedor fused with one or more R_(9a)'s; R_(9a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo, ═O,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀,—OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a); R₁₀, at each occurrence, isindependently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a), and the heterocyclyl andheterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl; R₁₄, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl, wherein the alkyl,cycloalkyl, aryl or arylalkyl may be optionally substituted with 0-3R_(14a); R_(14a), at each occurrence, is independently selected fromalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅,—S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and R₁₅, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl.
 6. The compound of claim1, wherein: X is —C(O)OH, —C(═O)NR₉R₉, or tetrazolyl; W is absent,(—CR_(8a)R_(8b)—)_(m), (—CR_(8a)R_(8b))_(m)—O— or alkenyl, wherein thealkenyl may be optionally substituted with one or more R_(8a)'s; m is1-2; Z is aryl or arylalkyl, all of which may be optionally substitutedwith one or more R₄'s; provided that W and Z, or when W is absent, X andZ, are attached to the same carbon on Ring A; R₄, at each occurrence, isindependently selected from hydrogen, alkyl, aryl, alkenyl, alkynyl,cycloalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH,—OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(O)R₁₀, —NR₉C(O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈, wherein the alkyl,aryl, alkenyl, alkynyl or cycloalkyl may be optionally substituted withone or more R₅'s; R₅, at each occurrence, is independently selected fromhydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈; R₈, at eachoccurrence, is independently alkyl, aryl or heterocyclyl; R_(8a), ateach occurrence, is independently hydrogen, alkyl or aryl; R_(8b), ateach occurrence, is independently hydrogen, —C(═O)OH, alkyl, —OH, halo,—CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl may beoptionally substituted with one or more R_(9a)'s; or R_(8a) and R_(8b)are taken together with the carbon to which both are attached to form a3- to 7-membered ring, which may optionally contain 1-4 heteroatomsselected from N, O, and S and be optionally substituted with 0-3 R_(9a);R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, whereinthe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl or heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; or two R₉'s together with the nitrogen to which they areattached form a unsaturated, saturated or partially saturated cyclicring system containing from 2-10 carbon atoms and from 0-4 additionalheteroatoms selected from N, O, S, S(O) and S(O)₂, wherein said ringsystem may be optionally substituted or fused with one or more R_(9a)'s;R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a); R₁₀,at each occurrence, is independently selected from alkyl, cycloalkyl,alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl,wherein the alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl may be optionally substituted with 0-3 R_(10a), andthe heterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selectedfrom N, O, and S; R_(10a), at each occurrence, is independently selectedfrom alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄,—S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, —NR₂S(O₂)R₈ or arylalkyl; R₁₄, at each occurrence, isindependently selected from hydrogen, alkyl, cycloalkyl, aryl orarylalkyl, wherein the alkyl, cycloalkyl, aryl or arylalkyl may beoptionally substituted with 0-3 R_(14a); R_(14a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅,—C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃,—C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅,—C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅, —S(═O)R₁₅,—S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ or arylalkyl; and R₁₅, at eachoccurrence, is independently selected from hydrogen, alkyl, cycloalkyl,aryl or arylalkyl.
 7. The compound of claim 1, wherein: X is —C(O)OH,—C(═O)NR₉R₉, or tetrazolyl; W is absent, (—CR_(8a)R_(8b)—)_(m),(—CR_(8a)R_(8b))_(m)—O— or alkenyl, wherein the alkenyl may beoptionally substituted with one or more R_(8a)'s; m is 1-2; Z is aryl orarylalkyl, all of which may be optionally substituted with one or moreR₄'s; provided that W and Z, or when W is absent, X and Z, are attachedto the same carbon on Ring A; R₄, at each occurrence, is independentlyselected from hydrogen, alkyl, aryl, alkenyl, cycloalkyl, halo, ═O,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀,—NR₉C(═O)OR₈ or —NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl orcycloalkyl may be optionally substituted with one or more R₅'s; R₅, ateach occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, alkenyl, cycloalkyl, cycloalkylalkyl, halo, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈; R₈, at each occurrence, is independently alkyl, aryl orheterocyclyl; R_(8a), at each occurrence, is independently hydrogen,alkyl or aryl; R_(8b), at each occurrence, is independently hydrogen,—C(═O)OH, alkyl, —OH, halo, —CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉,wherein the alkyl may be optionally substituted with one or moreR_(9a)'s; or R_(8a) and R_(8b) are taken together with the carbon towhich both are attached to form a 3- to 7-membered ring, which mayoptionally contain 1-4 heteroatoms selected from N, O, and S and beoptionally substituted with 0-3 R_(9a); R₉, at each occurrence, isindependently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-5 R_(9a), and the heterocyclyl or heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; or two R₉'s togetherwith the nitrogen to which they are attached form a unsaturated,saturated or partially saturated cyclic ring system containing from 2-10carbon atoms and from 0-4 additional heteroatoms selected from N, O, S,S(O) and S(O)₂, wherein said ring system may be optionally substitutedor fused with one or more R_(9a)'s; R_(9a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, alkenyl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN,—NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀,—OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a); R₁₀, at each occurrence, isindependently selected from alkyl, cycloalkyl, alkenyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a), and the heterocyclyl and heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; R_(10a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH,—SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ or arylalkyl; R₁₄, at eachoccurrence, is independently selected from hydrogen, alkyl, cycloalkyl,aryl or arylalkyl, wherein the alkyl, cycloalkyl, aryl or arylalkyl maybe optionally substituted with 0-3 R_(14a); R_(14a), at each occurrence,is independently selected from alkyl, haloalkyl, aryl, alkenyl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅,—C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃,—C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅,—C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(═O)R₁₅, —S(═O)R₁₅,—S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ or arylalkyl; and R₁₅, at eachoccurrence, is independently selected from hydrogen, alkyl, cycloalkyl,aryl or arylalkyl.
 8. The compound of claim 1, wherein: X is —C(═O)OH,or —C(═O)NR₉R₉; W is absent, (—CR_(8a)R_(8b)—)_(m),(—CR_(8a)R_(8b))_(m)—O— or alkenyl, wherein the alkenyl may beoptionally substituted with one or more R_(8a)'s; m is 1-2; Z is aryl orarylalkyl all of which may be optionally substituted with one or moreR₄'s; provided that W and Z, or when W is absent, X and Z, are attachedto the same carbon on Ring A; R₄, at each occurrence, is independentlyselected from hydrogen, alkyl, aryl, cycloalkyl, halo, ═O, —NH₂, —CN,—NO₂, —C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl or cycloalkyl may be optionallysubstituted with one or more R₅'s; R₅, at each occurrence, isindependently selected from hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(═O)OR₁₀,—OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈; R₈, at eachoccurrence, is independently alkyl, aryl or heterocyclyl; R_(8a), ateach occurrence, is independently hydrogen, alkyl or aryl; R_(8b), ateach occurrence, is independently hydrogen, —C(═O)OH, alkyl, —OH, halo,—CN, —OR₁₀, —C(═O)R₁₀ or —C(═O)NR₉R₉, wherein the alkyl may beoptionally substituted with one or more R_(9a)'s; or R_(8a) and R_(8b)are taken together with the carbon to which both are attached to form a3- to 7-membered ring, which may optionally contain 1-4 heteroatomsselected from N, O, and S and be optionally substituted with 0-3 R_(9a);R₉, at each occurrence, is independently hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, or heterocyclyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl or heterocyclyl may be optionallysubstituted with 0-5 R_(9a), and the heterocyclyl contains 1-4heteroatoms selected from N, O, and S; or two R₉'s together with thenitrogen to which they are attached form a unsaturated, saturated orpartially saturated cyclic ring system containing from 2-10 carbon atomsand from 0-4 additional heteroatoms selected from N, O, S, S(O) andS(O)₂, wherein said ring system may be optionally substituted or fusedwith one or more R_(9a)'s; R_(9a), at each occurrence, is independentlyselected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, andheterocyclylalkyl may be optionally substituted with 0-3 R_(10a); R₁₀,at each occurrence, is independently selected from alkyl, cycloalkyl,aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl,cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a), and the heterocyclyl andheterocyclylalkyl contain 1-4 heteroatoms selected from N, O, and S;R_(10a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl; R₁₄, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl, wherein the alkyl,cycloalkyl, aryl or arylalkyl may be optionally substituted with 0-3R_(14a); R_(14a), at each occurrence, is independently selected fromalkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₅, —OCF₃,—OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(O)R₁₅, —S(O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and R₁₅, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl, aryl or arylalkyl.
 9. The compound of claim1, wherein: X is —C(═O)OH, or —C(═O)NR₉R₉; W is absent,(—CR_(8a)R_(8b))_(m) or (—CR_(8a)R_(8b))_(m)—O—; m is 1-2; Z is aryl orarylalkyl, all of which may be optionally substituted with one or moreR₄'s provided that W and Z, or when W is absent, X and Z, are attachedto the same carbon on Ring A; R₄, at each occurrence, is independentlyselected from hydrogen, alkyl, aryl, cycloalkyl, halo, ═O, —NH₂, —CN,—NO₂, —C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl or cycloalkyl halo may beoptionally substituted with one or more R₅'s; R₅, at each occurrence, isindependently selected from hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(═O)OR₁₀,—OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈; R₈, at eachoccurrence, is independently alkyl, aryl or heterocyclyl; R_(8a), ateach occurrence, is independently hydrogen, alkyl or aryl; R_(8b), ateach occurrence, is independently hydrogen, —C(═O)OH, alkyl, —OH, halo,—CN, —OR₁₀ or —C(O)NR₉R₉, wherein the alkyl may be optionallysubstituted with one or more R_(9a)'s; or R₉, at each occurrence, isindependently hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, orheterocyclyl, wherein the alkyl, cycloalkyl, aryl, arylalkyl orheterocyclyl may be optionally substituted with 0-5 R_(9a), and theheterocyclyl contains 1-4 heteroatoms selected from N, O, and S; or twoR₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s; R_(9a), ateach occurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo, ═O,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀,—OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl may beoptionally substituted with 0-3 R_(10a); R₁₀, at each occurrence, isindependently selected from alkyl, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a), and the heterocyclyl and heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; R_(10a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo,—NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(O)R₁₄, —S(O)R₁₄,—S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ or arylalkyl; R₁₄, at eachoccurrence, is independently selected from hydrogen, alkyl, cycloalkyl,or aryl, wherein the alkyl, cycloalkyl or aryl may be optionallysubstituted with 0-3 R_(14a); R_(14a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅,—NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅,—S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃,—C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(O)R₁₅, —S(O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈,—NR₁₅S(O₂)R₈ or arylalkyl; and R₁₅, at each occurrence, is independentlyselected from hydrogen, alkyl, cycloalkyl or aryl.
 10. The compound ofclaim 1, wherein: X is —C(═O)OH, or —C(═O)NR₉R₉; W is absent,(—CR_(8a)R_(8b))_(m) or (—CR_(8a)R_(8b))_(m)—O—; m is 1-2; Z is aryl orarylalkyl, both of which may be optionally substituted with one or moreR₄'s; provided that W and Z, or when W is absent, X and Z, are attachedto the same carbon on Ring A; R₄, at each occurrence, is independentlyselected from hydrogen, alkyl, aryl, cycloalkyl, halo, ═O, —NH₂, —CN,—NO₂, —C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈, wherein the alkyl, aryl or cycloalkyl may be optionallysubstituted with one or more R₅'s; R₅, at each occurrence, isindependently selected from hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(O)R₁₀, —NR₉C(O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈; R₈, at each occurrence, is independently alkyl, aryl orheterocyclyl; R_(8a), at each occurrence, is independently hydrogen,alkyl or aryl; R_(8b), at each occurrence, is independently hydrogen,—C(═O)OH, alkyl, —OH, halo, —CN, —OR₁₀ or —C(O)NR₉R₉, wherein the alkylmay be optionally substituted with one or more R_(9a)'s; or R₉, at eachoccurrence, is independently hydrogen, alkyl, alkoxy, cycloalkyl, arylor heterocyclyl, wherein the alkyl, cycloalkyl, aryl or heterocyclyl maybe optionally substituted with 0-5 R_(9a), and the heterocyclyl contains1-4 heteroatoms selected from N, O, and S; or two R₉'s together with thenitrogen to which they are attached form a unsaturated, saturated orpartially saturated cyclic ring system containing from 2-10 carbon atomsand from 0-4 additional heteroatoms selected from N, O, S, S(O) andS(O)₂, wherein said ring system may be optionally substituted or fusedwith one or more R_(9a)'s; R_(9a), at each occurrence, is independentlyselected from alkyl, haloalkyl, aryl, cycloalkyl, cycloalkylalkyl,heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl,wherein the alkyl, aryl, cycloalkyl, cycloalkylalkyl and heterocyclylmay be optionally substituted with 0-3 R_(10a); R₁₀, at each occurrence,is independently selected from alkyl, cycloalkyl, aryl, arylalkyl,heterocyclyl or heterocyclylalkyl, wherein the alkyl, cycloalkyl, aryl,arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a), and the heterocyclyl and heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; R_(10a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄,—S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(O)R₁₄, —S(O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈,—NR₁₄S(O₂)R₈ or arylalkyl; R₁₄, at each occurrence, is independentlyselected from hydrogen, alkyl, cycloalkyl, or aryl, wherein the alkyl,cycloalkyl or aryl may be optionally substituted with 0-3 R₁₄; R_(14a),at each occurrence, is independently selected from alkyl, haloalkyl,aryl, cycloalkyl, cycloalkylalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₅, —OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅,—NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅, —NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅,—S(O)₂NR₁₅C(═O)OR₁₅, —S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃,—C(═O)R₁₅, —NR₁₅C(═O)R₁₅, —OC(O)R₁₅, —S(O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈,—NR₁₅S(O₂)R₈ or arylalkyl; and R₁₅, at each occurrence, is independentlyselected from hydrogen, alkyl, cycloalkyl or aryl.
 11. The compound ofclaim 1, wherein: X is —C(═O)NR₉R₉; W is absent, (—CR_(8a)R_(8b))_(m) or(—CR_(8a)R_(8b))_(m)—O—; m is 1-2; Z is aryl or arylalkyl, both of whichmay be optionally substituted with one or more R₄'s; provided that W andZ, or when W is absent, X and Z, are attached to the same carbon on RingA; R₄, at each occurrence, is independently selected from hydrogen,alkyl, aryl, cycloalkyl, halo, ═O, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₀,—OR₁₀, —OH, —OCF₃, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈, wherein the alkyl,aryl or cycloalkyl may be optionally substituted with one or more R₅'s;R₅, at each occurrence, is independently selected from hydrogen, alkyl,haloalkyl, aryl, cycloalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀,—OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or—NR₉S(O₂)R₈; R₈, at each occurrence, is independently alkyl, aryl orheterocyclyl; R_(8a), at each occurrence, is independently hydrogen,alkyl or aryl; R_(8b), at each occurrence, is independently hydrogen,—C(═O)OH, alkyl, —OH, halo, —CN, —OR₁₀ or —C(O)NR₉R₉, wherein the alkylmay be optionally substituted with one or more R_(9a)'s; or R₉, at eachoccurrence, is independently hydrogen, alkyl, alkoxy, cycloalkyl, arylor heterocyclyl, wherein the alkyl, cycloalkyl, aryl or heterocyclyl maybe optionally substituted with 0-5 R_(9a), and the heterocyclyl contains1-4 heteroatoms selected from N, O, and S; or two R₉'s together with thenitrogen to which they are attached form a unsaturated, saturated orpartially saturated cyclic ring system containing from 2-10 carbon atomsand from 0-4 additional heteroatoms selected from N, O, S, S(O) andS(O)₂, wherein said ring system may be optionally substituted or fusedwith one or more R_(9a)'s; R_(9a), at each occurrence, is independentlyselected from alkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, halo,═O, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀,—OC(═O)NR₁₄R₁₄, —NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl,cycloalkyl and heterocyclyl may be optionally substituted with 0-3R_(10a); R₁₀, at each occurrence, is independently selected from alkyl,aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, wherein the alkyl,aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionallysubstituted with 0-3 R_(10a), and the heterocyclyl and heterocyclylalkylcontain 1-4 heteroatoms selected from N, O, and S; R_(10a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₄,—OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl; R₁₄, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl or aryl, wherein the alkyl, cycloalkyl oraryl may be optionally substituted with 0-3 R_(14a); R_(14a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₅,—OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and R₁₅, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl or aryl.
 12. The compound of claim 1,wherein: A is

 both of which are substituted with at least one R₄ other than hydrogen;X is —C(═O)NR₉R₉; W is absent or (—CR_(8a)R_(8b))_(m); m is 1-2; Z isaryl or arylalkyl, both of which may be optionally substituted with oneor more provided that W and Z, or when W is absent, X and Z, areattached to the same carbon on Ring A; R₄, at each occurrence, isindependently selected from hydrogen, alkyl, aryl, cycloalkyl, halo, ═O,—NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀,—NR₉C(═O)OR₈ or —NR₉S(O₂)R₈, wherein the alkyl, aryl or cycloalkyl maybe optionally substituted with one or more R₅'s; R₅, at each occurrence,is independently selected from hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈; R₈, at eachoccurrence, is independently alkyl, aryl or heterocyclyl; R_(8a), ateach occurrence, is independently hydrogen or alkyl; R_(8b), at eachoccurrence, is independently hydrogen, —C(═O)OH, alkyl, —OH, halo, —CN,—OR₁₀ or —C(O)NR₉R₉, wherein the alkyl may be optionally substitutedwith one or more R_(9a)'s; or R₉, at each occurrence, is independentlyhydrogen, alkyl, alkoxy, cycloalkyl, aryl or heterocyclyl, wherein thealkyl, cycloalkyl, aryl or heterocyclyl may be optionally substitutedwith 0-5 R_(9a), and the heterocyclyl contains 1-4 heteroatoms selectedfrom N, O, and S; or two R₉'s together with the nitrogen to which theyare attached form a unsaturated, saturated or partially saturated cyclicring system containing from 2-10 carbon atoms and from 0-4 additionalheteroatoms selected from N, O, S, S(O) and S(O)₂, wherein said ringsystem may be optionally substituted or fused with one or more R_(9a)'s;R_(9a), at each occurrence, is independently selected from alkyl,haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂,—C(O)OH, —C(O)OR₁₄, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀,—S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄,—NR₁₄C(═O)OR₁₀, —NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄,—NR₁₄C(═O)NR₁₄R₁₄ or arylalkyl, wherein the alkyl, aryl, cycloalkyl andheterocyclyl may be optionally substituted with 0-3 R_(10a); R₁₀, ateach occurrence, is independently selected from alkyl, aryl, arylalkylor heterocyclyl, wherein the alkyl, aryl, arylalkyl or heterocyclyl maybe optionally substituted with 0-3 R_(10a), and the heterocyclylcontains 1-4 heteroatoms selected from N, O, and S; R_(10a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₄,—OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ orarylalkyl; R₁₄, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl or aryl, wherein the alkyl, cycloalkyl oraryl may be optionally substituted with 0-3 R_(14a); R_(14a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(═O)OR₁₅,—OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, —NR₁₅S(O₂)R₈ orarylalkyl; and R₁₅, at each occurrence, is independently selected fromhydrogen, alkyl, cycloalkyl or aryl.
 13. The compound of claim 1,wherein: A is

 both of which are substituted with at least one R₄ other than hydrogen;X is —C(═O)NR₉R₉; W is absent or (—CR_(8a)R_(8b))_(m); m is 1; Z is arylor arylalkyl, both of which may be optionally substituted with one ormore R₄'s; provided that W and Z, or when W is absent, X and Z, areattached to the same carbon on Ring A; R₄, at each occurrence, isindependently selected from hydrogen, alkyl, aryl, cycloalkyl, halo, ═O,—NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀,—NR₉C(═O)OR₈ or —NR₉S(O₂)R₈, wherein the alkyl, aryl or cycloalkyl maybe optionally substituted with one or more R₅'s; R₅, at each occurrence,is independently selected from hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈; R₈, at eachoccurrence, is independently alkyl or aryl; R_(8a), at each occurrence,is independently hydrogen or alkyl; R_(8b), at each occurrence, isindependently hydrogen, —C(═O)OH, alkyl, —OH, halo, —CN or —OR₁₀,wherein the alkyl may be optionally substituted with one or moreR_(9a)'s; or R₉, at each occurrence, is independently hydrogen, alkyl,alkoxy, aryl or heterocyclyl, wherein the alkyl, aryl or heterocyclylmay be optionally substituted with 0-5 R_(9a), and the heterocyclylcontains 1-4 heteroatoms selected from N, O, and S; or two R₉'s togetherwith the nitrogen to which they are attached form a unsaturated,saturated or partially saturated cyclic ring system containing from 2-10carbon atoms and from 0-4 additional heteroatoms selected from N, O, S,S(O) and S(O)₂, wherein said ring system may be optionally substitutedor fused with one or more R_(9a)'s; R_(9a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, cycloalkyl,heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₄, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, or —NR₁₄C(═O)NR₁₄R₁₄, whereinthe alkyl, aryl, cycloalkyl and heterocyclyl may be optionallysubstituted with 0-3 R_(10a); R₁₀, at each occurrence, is independentlyselected from alkyl, aryl or heterocyclyl, wherein the alkyl, aryl orheterocyclyl may be optionally substituted with 0-3 R_(10a), and theheterocyclyl and heterocyclylalkyl contain 1-4 heteroatoms selected fromN, O, and S; R_(10a), at each occurrence, is independently selected fromalkyl, haloalkyl, aryl, cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂,—C(O)OH, —C(O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄,—NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₄,—S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃,—C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, or —NR₁₄S(O₂)R₈; R₁₄, at each occurrence, isindependently selected from hydrogen, alkyl or aryl, wherein the alkylor aryl may be optionally substituted with 0-3 R_(14a); R_(14a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₅,—OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, or —NR₁₅S(O₂)R₈; andR₁₅, at each occurrence, is independently selected from hydrogen, alkylor aryl.
 14. The compound of claim 1, wherein: A is

 both of which are substituted with at least one R₄ other than hydrogen;X is —C(═O)NR₉R₉; W is absent or (—CR_(8a)R_(8b))_(m); m is 1; Z is arylor arylalkyl, both of which may be optionally substituted with one ormore R₄'s; provided that W and Z, or when W is absent, X and Z, areattached to the same carbon on Ring A; R₄, at each occurrence, isindependently selected from hydrogen, alkyl, aryl, cycloalkyl, halo, ═O,—NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₀, —OR₁₀, —OH, —OCF₃, —SH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀, —S(O)₂R₁₀, —O—S(O)₂R₁₀,—NR₉C(═O)OR₈ or —NR₉S(O₂)R₈, wherein the alkyl, aryl or cycloalkyl maybe optionally substituted with one or more R₅'s; R₅, at each occurrence,is independently selected from hydrogen, alkyl, haloalkyl, aryl,cycloalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —S(═O)R₁₀,—S(O)₂R₁₀, —O—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈; R₈, at eachoccurrence, is independently alkyl or aryl; R_(8a), at each occurrence,is independently hydrogen or alkyl; R_(8b), at each occurrence, isindependently hydrogen, —C(═O)OH, alkyl, —OH, halo, —CN, or —OR₁₀; R₉,at each occurrence, is independently hydrogen, alkyl, alkoxy or aryl,wherein the alkyl or aryl may be optionally substituted with 0-5 R_(9a);or two R₉'s together with the nitrogen to which they are attached form aunsaturated, saturated or partially saturated cyclic ring systemcontaining from 2-10 carbon atoms and from 0-4 additional heteroatomsselected from N, O, S, S(O) and S(O)₂, wherein said ring system may beoptionally substituted or fused with one or more R_(9a)'s; R_(9a), ateach occurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, heterocyclyl, halo, ═O, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₄,—OCF₃, —OR₁₀, —OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄,—NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂R₁₄, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄,—OC(═O)R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄, —OS(O)₂R₁₄, —NR₁₄C(═O)OR₁₀,—NR₁₄S(O₂)R₈, —C(═O)R₁₀, —OC(═O)NR₁₄R₁₄, or —NR₁₄C(═O)NR₁₄R₁₄, whereinthe alkyl, aryl, cycloalkyl and heterocyclyl may be optionallysubstituted with 0-3 R_(10a); R₁₀, at each occurrence, is independentlyselected from alkyl or aryl, wherein the alkyl or aryl may be optionallysubstituted with 0-3 R_(10a); R_(10a), at each occurrence, isindependently selected from alkyl, haloalkyl, aryl, cycloalkyl,heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₄, —OCF₃, —OR₁₄,—OH, —SH, —SR₁₄, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₄, —S(O)₂NR₁₄C(═O)OR₁₄, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —S(═O)R₁₄,—S(O)₂R₁₄, —NR₁₄C(═O)OR₈, or —NR₁₄S(O₂)R₈; R₁₄, at each occurrence, isindependently selected from hydrogen, alkyl or aryl, wherein the alkylor aryl may be optionally substituted with 0-3 R_(14a); R_(14a), at eachoccurrence, is independently selected from alkyl, haloalkyl, aryl,cycloalkyl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(O)OH, —C(O)OR₁₅,—OCF₃, —OR₁₅, —OH, —SH, —SR₁₅, —C(═O)NR₁₅R₁₅, —NR₁₅R₁₅, —S(O)₂NR₁₅R₁₅,—NR₁₅S(O)₂CF₃, —C(═O)NR₁₅S(O)₂R₁₅, —S(O)₂NR₁₅C(═O)OR₁₅,—S(O)₂NR₁₅C(═O)NR₁₅R₁₅, —C(═O)NR₁₅S(O)₂CF₃, —C(═O)R₁₅, —NR₁₅C(═O)R₁₅,—OC(═O)R₁₅, —S(═O)R₁₅, —S(O)₂R₁₅, —NR₁₅C(═O)OR₈, or —NR₁₅S(O₂)R₈; andR₁₅, at each occurrence, is independently selected from hydrogen oralkyl.
 15. The compound of claim 1, wherein the compound is selectedfrom the group consisting of:


16. A pharmaceutical composition comprising a compound of claim
 1. 17.The pharmaceutical composition of claim 16 further comprising apharmaceutically acceptable carrier.
 18. The pharmaceutical compositionof claim 16 further comprising at least one additional therapeuticagent.
 19. The compound of claim 1, wherein the compound is selectedfrom the group consisting of:


20. A compound having the formula:

enantiomers, diastereomers, solvates, or salts thereof.
 21. Apharmaceutical composition comprising the compound of claim
 20. 22. Thepharmaceutical composition of claim 21 further comprising apharmaceutically acceptable carrier.
 23. The pharmaceutical compositionof claim 21 further comprising at least one additional therapeuticagent.
 24. A compound having the formula:

enantiomers, diastereomers, solvates, or salts thereof.
 25. Apharmaceutical composition comprising the compound of claim
 24. 26. Thepharmaceutical composition of claim 25 further comprising apharmaceutically acceptable carrier.
 27. The pharmaceutical compositionof claim 25 further comprising at least one additional therapeuticagent.